bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and Properties of Energetic Materials Based on 1,3‐Diazocyclopentane
Authors: Jin Xinghui , Xiao Menghui , Wang Changying , Zhang Chong , Zhou Jianhua , Hu Bingcheng
Published: November 2018

A family of biheterocyclic energetic materials based on 1,3‐diazocyclopentane were synthesized and characterized by IR, NMR, MS, and elemental analysis. The crystal structures of compounds 8 and 9 were determined by single‐crystal X‐ray diffraction. Heats of formation, detonation properties were calculated by isodesmic reactions and Kamlet–Jacobs equations, respectively. The safety parameters associated with impact sensitivity and friction sensitivity were also investigated. It is noteworthy that compounds 5 and 6 possess excellent detonation properties (detonation velocities were 8.89 and 8.66 km s–1; detonation pressures were 35.8 and 32.7 GPa, respectively) and acceptable sensitivities (impact sensitivities were 10 and 13 J; friction sensitivities were 103 and 87 N, respectively). In addition, electronic properties (such as frontier molecular orbitals, electronic densities and electrostatic potentials) of compounds 5 and 6 were also simulated accurately to give an assessment of their physicochemical properties.
Factors influencing the use of opioids for breakthrough cancer pain: A secondary analysis of the IOPS‐MS study
Authors: Mercadante Sebastiano , Adile Claudio , Masedu Francesco , Marchetti Paolo , Costanzi Andrea , Aielli Federica
Published: November 2018

Background

Controversies exist about the choice and the doses of opioid medication in breakthrough cancer pain (BTcP).

Methods

The aim was to assess factors influencing the use and the doses of opioids prescribed for BTcP. There was performed a secondary analysis of a national, multicentre study that involving 32 centres performed in patients having BTcP. Diagnosis of BTcP was based on a definite algorithm. Patients using opioids for background pain and for BTcP were selected. Average pain intensity and opioids used for background pain and BTcP, and adverse effects were assessed, as well as patient’s satisfaction and the grade of mucositis.

Results

The analysis was performed in 2,771 patients. Opioid doses given for BTcP were significantly associated with those given for background pain. No relationship between adverse effects and the use and the doses of opioids used for BTcP was found. Drugs and doses were not correlated to the grade of oral mucositis. Nasal fentanyl preparations provided the fastest meaningful pain relief in comparison with other fentanyl transmucosal preparations or morphine preparations (P = 0.000). The majority of patients were satisfied with opioid medications given for BTcP. Only 2.8% of patients reported adverse effects related to opioid medication used for BTcP. Age and gender were independently associated with dosages of some fentanyl products.

Conclusions

Opioids for BTcP were effective and safe in a large sample of cancer patients with different stages of disease. Doses of opioids proportional to doses used for background pain seem to guarantee both efficacy and safety.

Significance

The use of opioids for breakthough cancer pain was effective and safe in a large sample of advanced cancer patients recruited in different stages of disease and settings. Doses of opioids proportional to opioid doses used for background analgesia, seem to guarantee both effectiveness and safety.
The relative efficacy of mindfulness versus distraction: The moderating role of attentional bias
Authors: Shires Alice , Sharpe Louise , Newton John Toby R. O.
Published: November 2018

Background

This study investigated whether the ability to disengage quickly from pain‐related stimuli moderated the relative efficacy of a mindfulness‐based intervention versus distraction in response to an experimental pain task.

Methods

Participants (n = 100) completed a dot probe task with eye tracking and were then randomized (2:2:1) to receive a mindfulness‐based interoceptive exposure task (MIET), distraction instructions or no instructions (control group) before engaging in the cold pressor test.

Results

Participants who were allocated to the MIET condition reported a significantly higher pain threshold and distress than the distraction group, although not significantly higher than the control group. Those in the MIET group had improved tolerance compared to both the distraction and control groups. Difficulty disengaging from pain‐related stimuli, as measured by the duration of the first fixation on sensory words, was found to moderate the relative efficacy of mindfulness versus distraction in terms of pain threshold and distress, but not tolerance. Those with difficulty disengaging from sensory pain words benefited less from the MIET. Duration of first fixation on sensory and affective pain words were highly correlated, and duration of first fixation on affective pain words also moderated the relative efficacy of MIET and distraction on threshold, but not distress.

Conclusions

These results show that a single brief session of a mindfulness task was sufficient to change an acute pain experience in comparison with a distraction task, and that those who disengaged quickly from pain words benefited most.

Significance

This study demonstrated the efficacy of a novel, exposure‐based mindfulness technique for pain tolerance and showed that those who disengaged easily from pain stimuli benefited most. This brief task could be clinically useful, particularly for those who are not overly focused on their pain symptoms.
Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice
Authors: Ogata Yoshiki , Nemoto Wataru , Yamagata Ryota , Nakagawasai Osamu , Shimoyama Shuji , Furukawa Tomonori , Ueno Shinya , Tan‐No Koichi
Published: November 2018

Background

We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)‐induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1‐7), an N‐terminal fragment of Ang II, may attenuate the Ang II‐induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1‐7) can attenuate STZ‐induced diabetic neuropathic pain.

Methods

Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho‐p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit.

Results

The i.t. administration of Ang (1‐7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1‐7), whose effect was reversed by A779.

Conclusions

Our data demonstrate that Ang (1‐7) attenuates STZ‐induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation.

Significance

The ACE2/Ang (1‐7)/Mas receptor axis was down‐regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1‐7) attenuated the STZ‐induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.
Physicochemical Characteristics of Polypyrrole/(Glucose oxidase)/(Prussian Blue)‐based Biosensor Modified with Ni‐ and Co‐Hexacyanoferrates
Authors: Rekertaitė Asta Inesė , Valiūnienė Aušra , Virbickas Povilas , Ramanavicius Arunas
Published: November 2018

In this work, three types of electrodes suitable for amperometric glucose biosensors were designed. One type of electrode was based on bio‐selective layer of polypyrrole/(glucose oxidase)/(Prussian Blue) (Ppy/GOx/PB) and it was used as a control electrode regarding to which electrochemical properties of two other types of electrodes were compared. During the formation of Prussian blue layers graphite electrodes were additionally modified by Ni‐hexacyanoferrate (NiHCF) and by Co‐hexacyanoferrate (CoHCF) in order to design Ppy/GOx/PB‐NiHCF and Ppy/GOx/PB‐CoHCF electrodes, respectively. Some physicochemical characteristics of all three types of electrodes were evaluated and compared. The Ppy/GOx/PB‐NiHCF electrode showed wider linear range of the calibration curve than Ppy/GOx/PB and Ppy/GOx/PB‐CoHCF electrodes. The effect of temperature on analytical performance of the Ppy/GOx/PB‐NiHCF based biosensor has been evaluated and activation energy of enzyme catalysed reaction has been calculated within the temperature range of 15 °C to 30 °C.
Disposable Amperometric Immunosensor for the Determination of the E‐Cadherin Tumor Suppressor Protein in Cancer Cells and Human Tissues
Authors: Muñoz‐San Martín Cristina , Pedrero María , Manuel de Villena F. Javier , Garranzo‐Asensio María , Rodríguez Nuria , Domínguez Gemma , Barderas Rodrigo , Campuzano Susana , Pingarrón José M.
Published: November 2018

This paper describes the results obtained in the development of the first electrochemical immunosensor described to date for the detection of E‐cadherin (E‐cad) protein, a relevant biomarker of prognosis and metastasis in cancer, based on the use of magnetic microcarriers (MBs) and amperometric transduction at screen‐printed carbon electrodes (SPCEs). Thus, the determination of E‐cad protein involved the use of two specific antibodies against this protein (one of them labelled with HRP) in a sandwich configuration onto HOOC‐MBs. The magnetic bioconjugates were captured onto SPCEs and the amperometric transduction was performed using the H2O2/hydroquinone (HQ) system. Under optimal conditions, this bioplatform demonstrated a wide linear concentration range (0.50–25 ng mL−1) and a detection limit as low as 0.16 ng mL−1, well below the optimal cut‐off level for the E‐cad protein (defined as 10,000 ng mL−1 for soluble E‐cad levels in serum). The developed sensor also showed a good reproducibility among measurements with seven different sensors constructed in the same manner (RSD, 5.4 %), stability for more than 15 days and good specificity towards other proteins commonly found on biological samples. The applicability of this simple handling bioplatform for the direct determination of this protein in cell lysates with different metastatic potential and extracts from paraffined‐embedded human colorectal cancer tissues of different grade were also demonstrated.
A Facile Strategy for Construction of Sensor for Detection of Ondansetron and Investigation of its Redox Behavior and Thermodynamic Parameters
Authors: Zaabal Moufida , Doulache Merzak , Bakirhan Nurgul K. , Kaddour Samia , Saidat Boubakeur , Ozkan Sibel A.
Published: November 2018

A sodium dodecylsulfate‐doped polypyrrole (SDS‐PPy) film was elaborated on glassy carbon electrode (GCE) by an electrodeposition method in phosphate buffer solution (pH 2.0) containing pyrrole (Py) and sodium dodecyl sulfate (SDS). SDS‐PPy/GCE was used for the construction of sensor, which showed excellent electrochemical response for the detection of ondansetron (OND) compared to conventional PPy. The application of the square wave (SW), with the adsorptive accumulation, indicates a maximum response at 1.33 V in H2SO4 (0.5 M). The influence of experimental parameters on determination of OND is discussed. The adsorptive stripping technique showed to be more sensitive, giving responses twice as big as those of non‐accumulated OND. The substantial improvement of response permits the development of an electroanalytical technique with a linear concentration in the range (1.0–80 μM), low detection (0.09 μM), and quantification limits (0.3 μM), and acceptable relative standard deviations of repeatability (0.59 %), and reproducibility (1.51 %). Consequently, this electrode is promising candidate for an accurate electroanalytical determination of OND in pharmaceutical samples with high sensitivity and selectivity, good accuracy and precision. The electrooxidation of OND at SDS‐PPy/GCE at various temperatures were studied by cyclic voltammetry to evaluate both the kinetic (ks and Ea) and thermodynamic (ΔG*, ΔH* and ΔS*) parameters.
Spatial models for non‐Gaussian data with covariate measurement error
Authors: Tadayon Vahid , Torabi Mahmoud
Published: November 2018

Spatial models have been widely used in the public health setup. In the case of continuous outcomes, the traditional approaches to model spatial data are based on the Gaussian distribution. This assumption might be overly restrictive to represent the data. The real data could be highly non‐Gaussian and may show features like heavy tails and/or skewness. In spatial data modeling, it is also commonly assumed that the covariates are observed without errors, but for various reasons, such as measurement techniques or instruments used, uncertainty is inherent in spatial (especially geostatistics) data, and so, these data are susceptible to measurement errors in the covariates of interest. In this paper, we introduce a general class of spatial models with covariate measurement error that can account for heavy tails, skewness, and uncertainty of the covariates. A likelihood method, which leads to the maximum likelihood estimation approach, is used for inference through the Monte Carlo expectation–maximization algorithm. The predictive distribution at nonsampled sites is approximated based on the Markov chain Monte Carlo algorithm. The proposed approach is evaluated through a simulation study and by a real application (particulate matter data set).
Performances of Plasma Sprayed Metal‐supported Solid Oxide Fuel Cell and Stack
Authors: Tsai C. H. , Hwang C. S. , Chang C. L. , Wu S. H. , Lin H. H. , Shiu W. H. , Lin J. K. , Yang S. F. , Fu C. Y. , Yang C. S.
Published: November 2018

The metal‐supported solid oxide fuel cell (MS‐SOFC) consisting of a porous Ni‐Mo as metal‐support, a La0.75Sr0.25Cr0.5Mn0.5O3–δ (LSCM) as diffusion barrier layer, a nano‐structured Ce0.55La0.45O3–δ (LDC)‐Ni as anode layer, a LDC as anode interlayer, a La0.8Sr0.2Ga0.8Mg0.2O3–δ (LSGM) as electrolyte, a Sm0.15Ce0.85O3–δ (SDC) as cathode interlayer, a 50 wt.% SDC–50 wt.% Sm0.5Sr0.5CoO3–δ (SSC) as composite cathode interlayer and a 25 wt.% SDC–75 wt.% SSC as cathode current collector are prepared by atmospheric plasma spraying (APS). The 25 cm2 cell delivers maximum power densities of 962 and 1,119 mW cm−2 at 700 and 750 °C. The durability, thermal cycling and redox cycling tests of this cell show the cell have good durability, thermal cycle stability and redox stability. The assembled single cell stack of 100 cm2 cell shows electric output powers of 39 W (481 mW cm−2) and 27.4 W (338 mW cm−2) at 750 °C and 700 °C. The long‐term stability test of this single cell stack shows a degradation rate of about 0.77% k−1 h−1 over 1,770 h at 400 mA cm−2 and 700 °C. Furthermore, a 25‐cell MS‐SOFC stack is assembled to evaluate the power performance and it shows a stack power of 829.8 W at 19.85 V and 740 °C.
Using soil survey data as a predictive tool for locating deeply buried archaeological deposits in stream valleys of the Midwest, United States
Authors: Layzell Anthony L. , Mandel Rolfe D.
Published: November 2018

In stream valleys of the US Midwest, most of the existing record of prehistoric cultures is deeply buried. Therefore, there is a need for understanding the age and distribution of different landform sediment assemblages (LSAs) in these settings to adequately evaluate the landscape for buried archaeological materials. In this study, we show the applicability of US Department of Agriculture Natural Resources Conservation Service soil survey data to (a) provide information on the spatial distribution and characteristics of different LSAs and (b) determine the associated geologic potential for buried cultural deposits. We considered four factors in our assessment, including the age of sedimentary deposits, soil stratigraphy, depositional environment, and drainage conditions. These data were used to develop a GIS‐based predictive model that was verified with data from a large volume of geoarchaeological research conducted throughout the region. The spatial scale of soil survey data, the uncertain nature of soil mapping, and the ability to detect the presence or absence of buried soils were found to be important limitations. Nevertheless, our results show that soil survey data can be useful as each of the four factors is considered to discriminate particular LSAs and appropriately evaluate buried‐site potential. Our approach can be broadly applied to fluvial systems where cultural deposits are deeply buried, particularly in other countries where soil survey databases exist.
The inferior occipital gyrus is a major cortical source of the face‐evoked N170: Evidence from simultaneous scalp and intracerebral human recordings
Authors: Jacques Corentin , Jonas Jacques , Maillard Louis , Colnat‐Coulbois Sophie , Koessler Laurent , Rossion Bruno
Published: November 2018

The sudden onset of a face image leads to a prominent face‐selective response in human scalp electroencephalographic (EEG) recordings, peaking 170 ms after stimulus onset at occipito–temporal (OT) scalp sites: the N170 (or M170 in magnetoencephalography). According to a widely held view, the main cortical source of the N170 lies in the fusiform gyrus (FG), whereas the posteriorly located inferior occipital gyrus (IOG) would rather generate earlier face‐selective responses. Here, we report neural responses to upright and inverted faces recorded in a unique patient using multicontact intracerebral electrodes implanted in the right IOG and in the OT sulcus above the right lateral FG (LFG). Simultaneous EEG recordings on the scalp identified the N170 over the right OT scalp region. The latency and amplitude of this scalp N170 were correlated at the single‐trial level with the N170 recorded in the lateral IOG, close to the scalp lateral occipital surface. In addition, a positive component maximal around the latency of the N170 (a P170) was prominent above the internal LFG, whereas this region typically generates an N170 (or “N200”) over its external/ventral surface. This suggests that electrophysiological responses in the LFG manifest as an equivalent dipole oriented mostly along the vertical axis with likely minimal projection to the lateral OT scalp region. Altogether, these observations provide evidence that the IOG is a major cortical generator of the face‐selective scalp N170, qualifying the potential contribution of the FG and questioning a strict serial spatiotemporal organization of the human cortical face network.
Analysis of streamflow droughts using fixed and variable thresholds
Authors: Sarailidis Georgios , Vasiliades Lampros , Loukas Athanasios
Published: November 2018

Hydrological drought analysis is very important in the design of hydrotechnical projects and water resources management and planning. In this study, a methodology is proposed for the analysis of streamflow droughts using the threshold level approach. The method has been applied to Yermasoyia semiarid basin in Cyprus based on 30‐year daily discharge data. Severity was defined as the accumulated water deficit volume occurring during a drought event, in respect with a target threshold. Fixed and variable thresholds (seasonal, monthly, and daily) were employed to derive the drought characteristics. The threshold levels were determined based on the Q50 percentiles of flow extracted from the corresponding flow duration curves for each threshold. The aim is to investigate the sensitivity of these thresholds in the estimation of maximum drought severities for various return periods and the derivation of severity–duration–frequency curves. The block maxima and the peaks over threshold approaches were used to perform the extreme value analysis. Three pooling procedures (moving average, interevent time criterion, and interevent time and volume criterion) were employed to remove the dependent and minor droughts. The application showed that the interevent time and volume criterion is the most unbiased pooling method. Therefore, it was selected to estimate the drought characteristics. The results of this study indicate that monthly and daily variable thresholds are able to capture abnormal drought events that occur during the whole hydrological year whereas the other two, only the severe ones. They are also more sensitive in the estimation of maximum drought severities and the derivation of the curves because they incorporate better the effect of drought durations.
Drought hotspot analysis and risk assessment using probabilistic drought monitoring and severity–duration–frequency analysis
Authors: Samantaray Alok Kumar , Singh Gurjeet , Ramadas Meenu , Panda Rabindra Kumar
Published: November 2018

Drought hotspot identification requires continuous drought monitoring and spatial risk assessment. The present study analysed drought events in the agriculture‐dominated mid‐Mahanadi River Basin in Odisha, India, using crop water stress as a drought indicator. This drought index incorporated different factors that affect crop water deficit such as the cropping pattern, soil characteristics, and surface soil moisture. The drought monitoring framework utilized a relevance vector machine model‐based classification that provided the uncertainty associated with drought categorization. Using the proposed framework, drought hotspots are identified in the study region and compared with indices based on precipitation and soil moisture. Further, a bivariate copula is employed to model the agricultural drought characteristics and develop the drought severity–duration–frequency (S–D–F) relationships. The drought hotspot maps and S–D–F curves are developed for different locations in the region. These provided useful information on the site‐specific drought patterns and the characteristics of the devastating droughts of 2002 and 2012, characterized by an average drought duration of 7 months at several locations. The site‐specific risk of short‐ and long‐term agricultural droughts are then investigated using the conditional copula. The results suggest that the conditional return periods and the S–D–F curves are valuable tools to assess the spatial variability of drought risk in the region.
Integration of diffraction phase microscopy and Raman imaging for label‐free morpho‐molecular assessment of live cells
Authors: Pandey Rishikesh , Zhou Renjie , Bordett Rosalie , Hunter Ciera , Glunde Kristine , Barman Ishan , Valdez Tulio , Finck Christine
Published: November 2018

Label‐free quantitative imaging is highly desirable for studying live cells by extracting pathophysiological information without perturbing cell functions. Here, we demonstrate a novel label‐free multimodal optical imaging system with the capability of providing comprehensive morphological and molecular attributes of live cells. Our morpho‐molecular microscopy (3M) system draws on the combined strength of quantitative phase microscopy (QPM) and Raman microscopy to probe the morphological features and molecular fingerprinting characteristics of each cell under observation. While the commonr‐path geometry of our QPM system allows for highly sensitive phase measurement, the Raman microscopy is equipped with dual excitation wavelengths and utilizes the same detection and dispersion system, making it a distinctive multi‐wavelength system with a small footprint. We demonstrate the applicability of the 3M system by investigating nucleated and nonnucleated cells. This integrated label‐free platform has a promising potential in preclinical research, as well as in clinical diagnosis in the near future.
Oxidized graphene nanoparticles as a delivery system for the pro‐apoptotic sphingolipid C6 ceramide
Authors: Suhrland Cassandra , Truman Jean‐Philip , Obeid Lina M. , Sitharaman Balaji
Published: November 2018

Sphingolipids such as ceramide have attracted much attention as possible anticancer agents due to their potent pro‐apoptotic effects. However, due to their extreme hydrophobicity, there is currently no clinically approved delivery method for in vivo use as a therapeutic agent. To this end, we have developed a novel method for loading the short‐chain C6 ceramide onto oxidized graphene nanoribbons (O‐GNRs) and graphene nanoplatelets (GNPs). Mass spectrometry revealed loading efficiencies of 57% and 51.5% for C6 ceramide onto O‐GNRs and GNPs, respectively. The PrestoBlue viability assay revealed that 100 µg/mL of C6 ceramide‐loaded O‐GNRs and C6 ceramide‐loaded GNPs reduced HeLa cell viability by approximately 93% and approximately 76%, respectively, compared to untreated HeLa cells, while equal concentrations of these nanoparticles without C6 ceramide did not significantly reduce HeLa cell viability. We confirmed that this cytotoxicity was apoptotic in nature via capase‐3 activity and Hoechst staining. Using live‐cell confocal imaging with the fluorescent NBD‐ceramide loaded on O‐GNRs, we observed robust uptake into HeLa cells within 30 min while NBD‐ceramide on its own was uptaken much more rapidly. Transmission electron microscopy confirmed that C6 ceramide‐loaded O‐GNRs were actually entering cells. Taken together, these data show that O‐GNRs are a promising delivery agent for ceramide. To our knowledge, this study is the first to use such a loading method. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 25–37, 2019.
Development of novel three‐dimensional scaffolds based on bacterial nanocellulose for tissue engineering and regenerative medicine: Effect of processing methods, pore size, and surface area
Authors: Osorio Marlon , Fernández‐Morales Patricia , Gañán Piedad , Zuluaga Robín , Kerguelen Herbert , Ortiz Isabel , Castro Cristina
Published: November 2018

Despite the efforts focused on manufacturing biological engineering scaffolds for tissue engineering and regenerative medicine, a biomaterial that meets the necessary characteristics for these applications has not been developed to date. Bacterial nanocellulose (BNC) is an outstanding biomaterial for tissue engineering and regenerative medicine; however, BNC's applications have been focused on two‐dimensional (2D) medical devices, such as wound dressings. Given the need for three‐dimensional (3D) porous biomaterials, this work evaluates two methods to generate (3D) BNC scaffolds. The structural characteristics and physicochemical, mechanical, and cell behaviour properties were evaluated. Likewise, the effects of the pore size and surface area in the mechanical performance of BNC biomaterials and their cell response in a fibroblast cell line are discussed for the first time. In this study, a new method is proposed for the development of 3D BNC scaffolds using paraffin wax. This new method is less time‐consuming, more robust in removing the paraffin and less aggressive toward the BNC microstructure. Moreover, the biomaterial had regular porosity with good mechanical behaviour; the cells can adhere and increase in number without overcrowding. Regarding the pore size and surface area, highly interconnected porosities (measuring approximately 60 μm) and high surface area are advantageous for the biomaterial's mechanical properties and cell behaviour. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 348–359, 2019.
Potentiation of paclitaxel effect by resveratrol in human breast cancer cells by counteracting the 17β‐estradiol/estrogen receptor α/neuroglobin pathway
Authors: Cipolletti Manuela , Montalesi Emiliano , Nuzzo Maria Teresa , Fiocchetti Marco , Ascenzi Paolo , Marino Maria
Published: November 2018

Neuroglobin (NGB), an antiapoptotic protein upregulated by 17β‐estradiol (E2), is part of E2/estrogen receptor α (ERα) pathway pointed to preserve cancer cell survival in presence of microenvironmental stressors including chemotherapeutic drugs. Here, the possibility that resveratrol (Res), an anticancer plant polyphenol, could increase the susceptibility of breast cancer cells to paclitaxel (Pacl) by affecting E2/ERα/NGB pathway has been evaluated. In MCF‐7 and T47D (ERα‐positive), but not in MDA‐MB 231 (ERα‐negative) nor in SK‐N‐BE (ERα and ERβ positive), Res decreases NGB levels interfering with E2/ERα‐induced NGB upregulation and with E2‐induced ERα and protein kinase B phosphorylation. Although Res treatment does not reduce cell viability by itself, this compound potentiates Pacl proapoptotic effects. Notably, the increase of NGB levels by NGB expression vector transfection prevents Pacl or Res/Pacl effects. Taken together, these findings indicate a new Res‐based mechanism that acts on tumor cells impairing the E2/ERα/NGB signaling pathways and increasing cancer cell susceptibility to chemotherapeutic agent.
Pulsed electromagnetic fields regulate osteocyte apoptosis, RANKL/OPG expression, and its control of osteoclastogenesis depending on the presence of primary cilia
Authors: Wang Pan , Tang Chi , Wu Junjie , Yang Yuefan , Yan Zedong , Liu Xiyu , Shao Xi , Zhai Mingming , Gao Jie , Liang Shengru , Luo Erping , Jing Da
Published: November 2018

Growing evidence has shown that pulsed electromagnetic fields (PEMF) can modulate bone metabolism in vivo and regulate the activities of osteoblasts and osteoclasts in vitro. Osteocytes, accounting for 95% of bone cells, act as the major mechanosensors in bone for transducing external mechanical signals and producing cytokines to regulate osteoblastic and osteoclastic activities. Targeting osteocytic signaling pathways is becoming an emerging therapeutic strategy for bone diseases. We herein systematically investigated the changes of osteocyte behaviors, functions, and its regulation on osteoclastogenesis in response to PEMF. The osteocyte‐like MLO‐Y4 cells were exposed to 15 Hz PEMF stimulation with different intensities (0, 5, and 30 Gauss [G]) for 2 hr. We found that the cell apoptosis and cytoskeleton organization of osteocytes were regulated by PEMF with an intensity‐dependent manner. Moreover, PEMF exposure with 5 G significantly inhibited apoptosis‐related gene expression and also suppressed the gene and protein expression of the receptor activator of nuclear factor κB ligand/osteoprotegerin (RANKL/OPG) ratio in MLO‐Y4 cells. The formation, maturation, and osteoclastic bone‐resorption capability of in vitro osteoclasts were significantly suppressed after treated with the conditioned medium from PEMF‐exposed (5 G) osteocytes. Our results also revealed that the inhibition of osteoclastic formation, maturation, and bone‐resorption capability induced by the conditioned medium from 5 G PEMF‐exposed osteocytes was significantly attenuated after abrogating primary cilia in osteocytes using the polaris siRNA transfection. Together, our findings highlight that PEMF with 5 G can inhibit cellular apoptosis, modulate cytoskeletal distribution, and decrease RANKL/OPG expression in osteocytes, and also inhibit osteocyte‐mediated osteoclastogenesis, which requires the existence of primary cilia in osteocytes. This study enriches our basic knowledge for further understanding the biological behaviors of osteocytes and is also helpful for providing a more comprehensive mechanistic understanding of the effect of electromagnetic stimulation on bone and relevant skeletal diseases (e.g., bone fracture and osteoporosis).
Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia
Authors: Du Lihong , Wenning Larissa , Migoya Elizabeth , Xu Yan , Carvalho Brendan , Brookfield Kathleen , Witjes Han , de Greef Rik , Lumbiganon Pisake , Sangkomkamhang Ussanee , Titapant Vitaya , Duley Lelia , Long Qian , Oladapo Olufemi T.
Published: November 2018

Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large‐volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings. A 2‐compartment population pharmacokinetic (PK) model was developed to characterize serial PK data from 92 pregnant women with preeclampsia who received magnesium sulfate. Body weight and serum creatinine concentration had a significant impact on magnesium PK. The final PK model was used to simulate magnesium concentration profiles for the 2 standard regimens and several simplified alternative dosing regimens. The simulations suggest that intravenous regimens with loading doses of 8 g over 60 minutes followed by 2 g/h for 10 hours and 12 g over 120 minutes followed by 2 g/h for 8 hours (same total dose as the standard intravenous regimen but shorter treatment duration) would result in magnesium concentrations below the toxic range. For the intramuscular regimens, higher maintenance doses given less frequently (4 g intravenously + 10‐g intramuscular loading doses with maintenance doses of 8 g every 6 hours or 10 g every 8 hours for 24 hours) or removal of the intravenous loading dose (eg, 10 g intramusculary every 8 hours for 24 hours) may be reasonable alternatives. In addition, individualized dose adjustments based on body weight and serum creatinine were proposed for the standard regimens.
Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects
Authors: Wang Xiaodong , Wang Jing , Arora Sujata , Hughes Lorraine , Christensen Jennifer , Lu Sharon , Zhang Zhi‐Yi
Published: November 2018

Rolapitant (Varubi) is a neurokinin‐1 receptor antagonist approved for the prevention of chemotherapy‐induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin‐1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug‐drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open‐label, drug‐drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1‐hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration‐time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration‐time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant.
Board examination stress effect on diastolic function
Authors: Geraiely Babak , Tavoosi Anahita , Sattarzadeh Roya , Hassanbeigi Hamidreza , Larry Mehrdad
Published: November 2018

Background

To this date, effects of mental stress on cardiac function have not been clearly investigated. Although hemodynamic and neuroendocrine adverse effects of daily mental stress on cardiovascular morbidity and mortality have been reported, its direct impact on diastolic function of the heart has not been previously studied. In this study, we aimed to assess the role of Board Exam anxiety on right and left ventricular diastolic function in medical residents.

Methods

Forty medical residents prior to participation in the medical board exam were enrolled in our study. Right prior to as well as 2 month after the exam, all residents underwent trans‐thoracic Doppler echocardiography. Right ventricular systolic and diastolic functions and echocardiography indices were measured. Levels of anxiety were measured using Beck Anxiety Inventory Questionnaire before and after the exam. Pre exam and post exam results of study population as well as low and high anxiety groups were evaluated.

Results

Early to late mitral inflow velocity (E/A ratio) in LV inflow increased after board exam (P‐value <.001). E/A ratio in RV inflow increased after board exam (P‐value: .002). Early mitral inflow to its annular velocity (E/E’ ratio) in septal wall decreased after board exam (P‐value<.001). The change in E/E′ RV free wall did not reach statistical significance (P = .57). Mitral annuls velocities measured by TDI in septal and lateral wall and also tricuspid annulus velocity increased after board exam (P‐value<.05). The comparison of these changes between the high‐stress and low‐stress groups of residents revealed significant differences. Comparison of changes of E/A ratio in the mitral and tricuspid inflow as well as the E/E’ in the septum and free wall of the right ventricle before and after the Board Exam between high‐stress and low‐stress groups was not statistically significant, although there was a trend of more changes in high‐ stress group residents.

Conclusion

This is the first report of comprehensive sequential assessment of left and right ventricular diastolic functions during and after a real subacute stress occasion. The finding of a decreased E/A and E′ in response to mental stress suggests that repetitive mental stress may induce diastolic dysfunction which is a mechanism of diastolic heart failure in individuals at risk.
A circulation‐based approach considering non‐stationarities within the scope of statistical downscaling: An example of seasonal daily precipitation extremes in the Mediterranean area
Authors: Merkenschlager Christian , Hertig Elke
Published: November 2018

Non‐stationarities within the predictor–predictand relationships can substantially affect model skill of statistical downscaling approaches. For this reason, an approach is presented which takes varying predictor–predictand relationships explicitly into account. Seasonal aggregated daily precipitation extremes (90th, 95th and 99th quantiles) were assessed by means of 31‐year running contiguous calibration periods. Here, when the end of the time series was reached years from the beginning were attached. Thus, a regression model ensemble (RME) becomes available, with the number of established statistical models corresponding to the number of years within the time series. With respect to non‐stationarities in the projection periods, a novel approach is presented. A single model of the RME is determined for each sub‐period which seems to be the most suitable model (MSM) for assessing precipitation extremes within the respective period. In order to define the MSM weighted correlations of atmospheric circulation composites, represented by the geopotential heights, between reanalysis and model runs were calculated for all significant predictors. The reanalysis period which exhibits the highest mean correlation coefficient is then considered for the projections of the respective period of the model runs. Subsequently, a second selection process was performed in order to determine whether the regression model (RM) established within this period or the model with the highest skill within this period is used for assessing future precipitation extremes. Results have shown that projections can significantly differ depending on whether a non‐stationary or a stationary downscaling setup is used for the assessments.
Predicting agronomical and ecological effects of shifting from sheep to cattle grazing in highly dynamic Mediterranean dry grasslands
Authors: Faria Nuno
Published: November 2018

In the recent decades, cattle numbers strongly increased whereas sheep numbers decreased in south Portugal. This paper aims to predict the potential agronomical and ecological effects of these trends and clarify about the versatility of cattle and sheep systems in adapting to climate changes in the Mediterranean basin. We monitored livestock management in the dry grasslands of Évora (2012 to 2016) and investigated for the effect of livestock type (TLivest) on (a) sward's characteristics, (b) vegetation taxonomic diversity, and (c) in conforming vegetation communities and promoting species of agronomical interests (SAIs). Generalized linear mixed models were used to link management descriptors and vegetation parameters with TLivest. Redundancy analysis was used to analyse the changes due to TLivest on floristic composition and SAIs. Sheep fields presented (a) higher number of days under grazing and lower instantaneous stocking rates than cattle or mixed fields and (b) lower vegetation height in April in wet years and higher green vegetation cover in May; α‐ and γ‐diversity were poorly related with TLivest, but β‐diversity was lower under mixed grazing than under sheep or cattle grazing. The highest richness of legume species was found in permanent grasslands grazed by sheep. Redundancy analysis provided a good discrimination of TLivest but a poor segregation of vegetation communities. As a conclusion, sheep grazing can be seen as a more powerful tool to increase sward heterogeneity, and thus, a loss of grassland heterogeneity can be expected under cattle grazing. The lower versatility of cattle systems suggests narrower opportunities in adapting to climate change.
Life span pigmentation changes of the substantia nigra detected by neuromelanin‐sensitive MRI
Authors: Xing Yue , Sapuan Abdul , Dineen Rob A. , Auer Dorothee P.
Published: November 2018

Background: Neuromelanin is a pigment with strong iron‐chelating properties preferentially found in dopaminergic neurons of the substantia nigra pars compacta (SNpc). Parkinson's disease is characterized by pronounced, MRI‐detectable neuromelanin loss, but the neuroprotective or neurotoxic role of neuromelanin remains debated. Histological studies have demonstrated neuromelanin increases with age, but this has not been confirmed in vivo, and there is uncertainty whether neuromelanin declines, stabilizes, or increases from middle age.

Methods: This study aimed to establish physiological changes of pigmentation of the SNpc using a pooled data set of neuromelanin‐sensitive 3T MRI from 134 healthy individuals aged 5‐83 years. Neuromelanin‐related brightness (regional contrast to ratio) and calibrated hyperintense volumes were analyzed using linear and nonlinear regression models to characterize age effects. Laterality, sex, and subregional effects were also assessed.

Results: For brightness, age effects were best described as a quadratic trajectory explaining 81.5% of the observed variance in the SNpc showing a strong increase from childhood to adolescence, with plateauing in middle age and a decline in older age. Similar but less pronounced effects were seen in hyperintense volumes. We also show an anterior‐posterior gradient in SNpc contrast, larger normalized neuromelanin‐rich volume in women > 47 years old, but no laterality effect.

Conclusions: Using optimized neuromelanin MRI in a life span sample, we demonstrate a strong age effect with inverted U‐shaped SNpc pigmentation‐related contrast from childhood to old age. This age trajectory of physiological SNpc pigmentation needs to be taken into account for diagnostic applications of depigmentation. The study also paves the way for systematic investigations of the mechanisms of neuromelanin in healthy and pathological brain development and aging. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Multi‐model ensemble predictions of aviation turbulence
Authors: Storer Luke N. , Gill Philip G. , Williams Paul D.
Published: November 2018

Turbulence remains one of the leading causes of aviation incidents. Climate change is predicted to increase the occurrence of clear‐air turbulence and therefore forecasting turbulence will become more important in the future. Currently, the two World Area Forecast Centres (WAFCs) use deterministic numerical weather prediction models to predict clear‐air turbulence operationally; it has been shown that ensemble forecasts improve the forecast skill of traditional meteorological variables. This study applies multi‐model ensemble forecasting to aviation turbulence for the first time. It is shown in a 12‐month global trial from May 2016 to April 2017 that combining two different ensembles yields a similar forecast skill to a single model ensemble and yields an improvement in forecast value at low cost/loss ratios. This finding is consistent with previous work showing that the use of ensembles in turbulence forecasting is beneficial. Using a multi‐model approach is an effective way to improve the forecast skill and provide pilots and flight planners with more information about the forecast confidence, allowing them to make a more informed decision about what action needs to be taken, such as diverting around the turbulence or requiring passengers and flight attendants to fasten their seatbelts. The multi‐model ensemble approach is intended to be made operational by both WAFCs in the near future and this study lays the foundations to make this possible.
Radiobiological issues in prospective carbon ion therapy trials
Authors: Fossati Piero , Matsufuji Naruhiro , Kamada Tadashi , Karger Christian P.
Published: November 2018

Carbon ion radiotherapy (CIRT) is developing toward a versatile tool in radiotherapy; however, the increased relative biological effectiveness (RBE) of carbon ions in tumors and normal tissues with respect to photon irradiation has to be considered by mathematical models in treatment planning. As a consequence, dose prescription and definition of dose constraints are performed in terms of RBE weighted rather than absorbed dose. The RBE is a complex quantity, which depends on physical variables, such as dose and beam quality as well as on normal tissue‐ or tumor‐specific factors. At present, three RBE models are employed in CIRT: (a) the mixed‐beam model, (b) the Microdosimetric Kinetic Model (MKM), and (c) the local effect model. While the LEM is used in Europe, the other two models are employed in Japan, and unfortunately, the concepts of how the nominal RBE‐weighted dose is determined and prescribed differ significantly between the European and Japanese centers complicating the comparison, transfer, and reproduction of clinical results. This has severe impact on the way treatments should be prescribed, recorded, and reported. This contribution reviews the concept of the clinical application of the different RBE models and the ongoing clinical CIRT trials in Japan and Europe. Limitations of the RBE models and the resulting radiobiological issues in clinical CIRT trials are discussed in the context of current clinical evidence and future challenges.