Extracellular ATP signaling and clinical relevance

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen
Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.



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Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade

Publication date: Available online 20 December 2017
Source:Clinical Immunology
Author(s): Dino B.A. Tan, Teck-Hui Teo, Abdul M. Setiawan, Nathanael E. Ong, Maja Zimmermann, Alan Chen-Yu Hsu, Peter A.B. Wark, Yuben P. Moodley




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IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis

Publication date: Available online 21 December 2017
Source:Clinical Immunology
Author(s): Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff
ObjectivesB-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE).MethodsIsolated PBMCs of SLE-patients (n=30) and healthy controls (n=21) were in vitro stimulated with CPG, IgG+IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry.ResultsThe strongest stimulus for Granzyme B secretion of B-cells was IgG+IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B⁺ B-cells in particular SLE-patients with active disease and with lupus nephritis.ConclusionsThe frequency of GrB+ producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.



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Optical properties of implanted Xe color centers in diamond

Publication date: 15 March 2018
Source:Optics Communications, Volume 411
Author(s): Russell Sandstrom, Li Ke, Aiden Martin, Ziyu Wang, Mehran Kianinia, Ben Green, Wei-bo Gao, Igor Aharonovich
Optical properties of color centers in diamond have been the subject of intense research due to their promising applications in quantum photonics. In this work we study the optical properties of Xe related color centers implanted into nitrogen rich (type IIA) and an ultrapure, electronic grade diamond. The Xe defect has two zero phonon lines at ∼794 nm and 811 nm, which can be effectively excited using both green and red excitation, however, its emission in the nitrogen rich diamond is brighter. Near resonant excitation is performed at cryogenic temperatures and luminescence is probed under strong magnetic field. Our results are important towards the understanding of the Xe related defect and other near infrared color centers in diamond.



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Daily conformity drinking motivations are associated with increased odds of consuming alcohol mixed with energy drinks

Publication date: April 2018
Source:Addictive Behaviors, Volume 79
Author(s): Ashley N. Linden-Carmichael, Cathy Lau-Barraco
Recent research indicates that individuals drank more heavily and experienced more harms on days they consumed alcohol mixed with energy drinks (AmEDs). Limited research, thus far, has examined predictors of AmED use on a daily level. Drinking motives, or reasons for drinking, are shown to discern AmED users from non-users, but the extent to which daily drinking motives covary with AmED use has not been tested. The current study used a daily diary design to determine how motives differ between AmED and other drinking occasions. Participants included 122 college students (73.8% women) with a mean age of 20.39years. Participants completed up to 14 daily surveys, resulting in 389 drinking days (40days involved AmED use). Participants reported on their drinking motives at baseline as well as on each drinking day. Multilevel models revealed that, after controlling for other motives, AmED use was more likely on days where conformity motives were higher than usual and was less likely when enhancement motives were higher. Daily social and coping motives as well as all motives measured at baseline were unassociated with AmED use. Our findings suggest that conformity motives, or drinking to fit in with others, are the most salient drinking motive predicting AmED use on a drinking day. Given that conformity motives are often less associated with alcohol use outcomes in general, these findings highlight AmEDs as a unique alcoholic beverage. Clinicians and interventionists working with frequent AmED users should consider the unique conditions under which AmEDs are consumed.



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Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies

Publication date: Available online 20 December 2017
Source:Trends in Immunology
Author(s): Shashi Gujar, Jonathan G. Pol, Youra Kim, Patrick W. Lee, Guido Kroemer
Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics. Administration of OVs to cancer-bearing hosts induces two distinct immunities: antiviral and antitumor. While antitumor immunity is beneficial, antiviral immune responses are often considered detrimental for the efficacy of OV-based therapy. The existing dogma postulates that anti-OV immune responses restrict viral replication and spread, and thus reduce direct OV-mediated killing of cancer cells. Accordingly, a myriad of therapeutic strategies aimed at mitigating anti-OV immune responses is presently being tested. Here, we advocate that OV-induced antiviral immune responses hold intrinsic anticancer benefits and are essential for establishing clinically desired antitumor immunity. Thus, to achieve the optimal efficacy of OV-based cancer immunotherapies, strategic management of anti-OV immune responses is of critical importance.



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Mammography screening: A major issue in medicine

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Philippe Autier, Mathieu Boniol
Breast cancer mortality is declining in most high-income countries. The role of mammography screening in these declines is much debated.Screening impacts cancer mortality through decreasing the incidence of number of advanced cancers with poor prognosis, while therapies and patient management impact cancer mortality through decreasing the fatality of cancers. The effectiveness of cancer screening is the ability of a screening method to curb the incidence of advanced cancers in populations. Methods for evaluating cancer screening effectiveness are based on the monitoring of age-adjusted incidence rates of advanced cancers that should decrease after the introduction of screening. Likewise, cancer-specific mortality rates should decline more rapidly in areas with screening than in areas without or with lower levels of screening but where patient management is similar. These two criteria have provided evidence that screening for colorectal and cervical cancer contributes to decreasing the mortality associated with these two cancers. In contrast, screening for neuroblastoma in children was discontinued in the early 2000s because these two criteria were not met. In addition, overdiagnosis – i.e. the detection of non-progressing occult neuroblastoma that would not have been life-threatening during the subject's lifetime – is a major undesirable consequence of screening.Accumulating epidemiological data show that in populations where mammography screening has been widespread for a long time, there has been no or only a modest decline in the incidence of advanced cancers, including that of de novo metastatic (stage IV) cancers at diagnosis. Moreover, breast cancer mortality reductions are similar in areas with early introduction and high penetration of screening and in areas with late introduction and low penetration of screening. Overdiagnosis is commonplace, representing 20% or more of all breast cancers among women invited to screening and 30–50% of screen-detected cancers. Overdiagnosis leads to overtreatment and inflicts considerable physical, psychological and economic harm on many women. Overdiagnosis has also exerted considerable disruptive effects on the interpretation of clinical outcomes expressed in percentages (instead of rates) or as overall survival (instead of mortality rates or stage-specific survival). Rates of radical mastectomies have not decreased following the introduction of screening and keep rising in some countries (e.g. the United States of America (USA)). Hence, the epidemiological picture of mammography screening closely resembles that of screening for neuroblastoma.Reappraisals of Swedish mammography trials demonstrate that the design and statistical analysis of these trials were different from those of all trials on screening for cancers other than breast cancer. We found compelling indications that these trials overestimated reductions in breast cancer mortality associated with screening, in part because of the statistical analyses themselves, in part because of improved therapies and underreporting of breast cancer as the underlying cause of death in screening groups. In this regard, Swedish trials should publish the stage-specific breast cancer mortality rates for the screening and control groups separately. Results of the Greater New York Health Insurance Plan trial are biased because of the underreporting of breast cancer cases and deaths that occurred in women who did not participate in screening. After 17 years of follow-up, the United Kingdom (UK) Age Trial showed no benefit from mammography screening starting at age 39–41.Until around 2005, most proponents of breast screening backed the monitoring of changes in advanced cancer incidence and comparative studies on breast cancer mortality for the evaluation of breast screening effectiveness. However, in an attempt to mitigate the contradictions between results of mammography trials and population data, breast-screening proponents have elected to change the criteria for the evaluation of cancer screening effectiveness, giving precedence to incidence-based mortality (IBM) and case—control studies. But practically all IBM studies on mammography screening have a strong ecological component in their design. The two IBM studies done in Norway that meet all methodological requirements do not document significant reductions in breast cancer mortality associated with mammography screening. Because of their propensity to exaggerate the health benefits of screening, case–control studies may demonstrate that mammography screening could reduce the risk of death from diseases other than breast cancer.Numerous statistical model approaches have been conducted for estimating the contributions of screening and of patient management to reductions in breast cancer mortality. Unverified assumptions are needed for running these models. For instance, many models assume that if screening had not occurred, the majority of screen-detected asymptomatic cancers would have progressed to symptomatic advanced cancers. This assumption is not grounded in evidence because a large proportion of screen-detected breast cancers represent overdiagnosis and hence non-progressing tumours. The accumulation of population data in well-screened populations diminishes the relevance of model approaches.The comparison of the performance of different screening modalities – e.g. mammography, digital mammography, ultrasonography, magnetic resonance imaging (MRI), three-dimensional tomosynthesis (TDT) – concentrates on detection rates, which is the ability of a technique to detect more cancers than other techniques. However, a greater detection rate tells little about the capacity to prevent interval and advanced cancers and could just reflect additional overdiagnosis. Studies based on the incidence of advanced cancers and on the evaluation of overdiagnosis should be conducted before marketing new breast-imaging technologies.Women at high risk of breast cancer (i.e. 30% lifetime risk and more), such as women with BRCA1/2 mutations, require a close breast surveillance. MRI is the preferred imaging method until more radical risk-reduction options are eventually adopted. For women with an intermediate risk of breast cancer (i.e. 10–29% lifetime risk), including women with extremely dense breast at mammography, there is no evidence that more frequent mammography screening or screening with other modalities actually reduces the risk of breast cancer death.A plethora of epidemiological data shows that, since 1985, progress in the management of breast cancer patients has led to marked reductions in stage-specific breast cancer mortality, even for patients with disseminated disease (i.e. stage IV cancer) at diagnosis. In contrast, the epidemiological data point to a marginal contribution of mammography screening in the decline in breast cancer mortality. Moreover, the more effective the treatments, the less favourable are the harm–benefit balance of screening mammography.New, effective methods for breast screening are needed, as well as research on risk-based screening strategies.



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Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): K. Strasser-Weippl, G. Sudan, R. Ramjeesingh, L.E. Shepherd, J. O'Shaughnessy, W.R. Parulekar, P.E.R. Liedke, B.E. Chen, P.E. Goss
BackgroundHistological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer.MethodsClinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS).ResultsA total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79–1.63], P = 0.49 and HR 1.04, 95% CI [0.77–1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73–1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98–3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99–4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00–4.31], P = 0.05).ConclusionOur data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC.Clinical Trial informationNCT00066573.



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The subgroups of the phase III RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo with best supportive care in patients with metastatic colorectal cancer

Publication date: February 2018
Source:European Journal of Cancer, Volume 90
Author(s): Eric Van Cutsem, Robert J. Mayer, Stéphanie Laurent, Robert Winkler, Cristina Grávalos, Manuel Benavides, Federico Longo-Munoz, Fabienne Portales, Fortunato Ciardiello, Salvatore Siena, Kensei Yamaguchi, Kei Muro, Tadamichi Denda, Yasushi Tsuji, Lukas Makris, Patrick Loehrer, Heinz-Josef Lenz, Atsushi Ohtsu
BackgroundIn the phase III RECOURSE trial, trifluridine/tipiracil (TAS-102) extended overall survival (OS) and progression-free survival (PFS) with an acceptable toxicity profile in patients with metastatic colorectal cancer refractory or intolerant to standard therapies. The present analysis investigated the efficacy and safety of trifluridine/tipiracil in RECOURSE subgroups.MethodsPrimary and key secondary end-points were evaluated using a Cox proportional hazards model in prespecified subgroups, including geographical subregion (United States of America [USA], European Union [EU], Japan), age (<65 years, ≥65 years) and v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) status (wild type, mutant). Safety and tolerability were reported with descriptive statistics.ResultsEight-hundred patients were enrolled: USA, n = 99; EU, n = 403; Japan, n = 266. Patients aged ≥65 years and those with mutant KRAS tumours comprised 44% and 51% of all patients in the subregions, respectively. Final OS analysis (including 89% of events, compared with 72% in the initial analysis) confirmed the survival benefit associated with trifluridine/tipiracil, with a hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.59–0.81; P = 0.0001). Median OS in the three regions was 6.5–7.8 months in the trifluridine/tipiracil arm and 4.3–6.7 months in the placebo arm (USA: HR 0.56; 95% CI 0.34–0.94; P = 0.0277; EU: HR 0.62; 95% CI 0.48–0.80; P = 0.0002; Japan: HR 0.75; 95% CI 0.57–1.00; P = 0.0470). Median PFS was 2.0–2.8 months for trifluridine/tipiracil and 1.7–1.8 months for placebo; HRs favoured trifluridine/tipiracil in all regions. Similar clinical benefits of trifluridine/tipiracil were observed in elderly patients and in those with mutant KRAS tumours. There were no marked differences among subregions in terms of safety and tolerability.ConclusionsTrifluridine/tipiracil was effective in all subgroups, regardless of age, geographical origin or KRAS status.This trial is registered with ClinicalTrials.gov: NCT01607957.



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miRNA delivery for skin wound healing

Publication date: Available online 19 December 2017
Source:Advanced Drug Delivery Reviews
Author(s): Zhao Meng, Dezhong Zhou, Yongsheng Gao, Ming Zeng, Wenxin Wang
The wound healing has remained a worldwide challenge as one of significant public health problems. Pathological scars and chronic wounds caused by injury, aging or diabetes lead to impaired tissue repair and regeneration. Due to the unique biological wound environment, the wound healing is a highly complicated process, efficient and targeted treatments are still lacking. Hence, research-driven to discover more efficient therapeutics is a highly urgent demand. Recently, the research results have revealed that microRNA (miRNA) is a promising tool in therapeutic and diagnostic fields because miRNA is an essential regulator in cellular physiology and pathology. Therefore, new technologies for wound healing based on miRNA have been developed and miRNA delivery has become a significant research topic in the field of gene delivery.

Graphical abstract

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Considering factors affecting the connectome-based identification process: Comment on Waller et al.

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Corey Horien, Stephanie Noble, Emily S. Finn, Xilin Shen, Dustin Scheinost, R. Todd Constable
A recent study by Waller and colleagues evaluated the reliability, specificity, and generalizability of using functional connectivity data to identify individuals from a group. The authors note they were able to replicate identification rates in a larger version of the original Human Connectome Project (HCP) dataset. However, they also report lower identification accuracies when using historical neuroimaging acquisitions with low spatial and temporal resolution. The authors suggest that their results indicate connectomes derived from historical imaging data may be similar across individuals, to the extent that this connectome-based approach may be inappropriate for precision psychiatry and the goal of drawing inferences based on subject-level data. Here we note that the authors did not take into account factors affecting data quality and hence identification rates, independent of whether a low spatiotemporal resolution acquisition or a high spatiotemporal resolution acquisition is used. Specifically, we show here that the amount of data collected per subject and in-scanner motion are the predominant factors influencing identification rates, not the spatiotemporal resolution of the acquisition. To do this, we investigated identification rates in the HCP dataset as a function of the amount of data and motion. Using a dataset from the Consortium for Reliability and Reproducibility (CoRR), we investigated the impact of multiband versus non-multiband imaging parameters; that is, high spatiotemporal resolution versus low spatiotemporal resolution acquisitions. We show scan length and motion affect identification, whereas the imaging protocol does not affect these rates. Our results suggest that motion and amount of data per subject are the primary factors impacting individual connectivity profiles, but that within these constraints, individual differences in the connectome are readily observable.



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Gas-free calibrated fMRI with a correction for vessel-size sensitivity

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Avery J.L. Berman, Erin L. Mazerolle, M. Ethan MacDonald, Nicholas P. Blockley, Wen-Ming Luh, G. Bruce Pike
Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology.



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Affective value, intensity and quality of liquid tastants/food discernment in the human brain: An activation likelihood estimation meta-analysis

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Andy Wai Kan Yeung, Tazuko K. Goto, W. Keung Leung
The primary dimensions of taste are affective value, intensity and quality. Numerous studies have reported the role of the insula in evaluating these dimensions of taste; however, the results were inconsistent. Therefore, in the current study, we performed meta-analyses of published data to identify locations consistently activated across studies and evaluate whether different regions of the human brain could be responsible for processing different dimensions of taste. Meta-analyses were performed on 39 experiments, with 846 total healthy subjects (without psychiatric/neurological disorders) in 34 studies reporting whole-brain results. The aim was to establish the activation likelihood estimation (ALE) of taste-mediated regional activation across the whole brain. Apart from one meta-analysis for all studies in general, three analyses were performed to reveal the clusters of activation that were attributable to processing the affective value (data from 323 foci), intensity (data from 43 foci) and quality (data from 45 foci) of taste. The ALE revealed eight clusters of activation outside the insula for processing affective value, covering the middle and posterior cingulate, pre-/post-central gyrus, caudate and thalamus. The affective value had four clusters of activation (two in each hemisphere) in the insula. The intensity and quality activated only the insula, each with one cluster on the right. The concurrence between studies was moderate; at best, 53% of the experiments contributed to the significant clusters attributable to the affective value, 60% to intensity and 50% to quality. The affective value was processed bilaterally in the anterior to middle insula, whereas intensity was processed in the right antero-middle insula, and quality was processed in the right middle insula. The right middle dorsal insula was responsible for processing both the affective value and quality of taste. The exploratory analysis on taste quality did not have a significant result if the studies using liquid food stimuli were excluded. Results from the meta-analyses on studies involving the oral delivery of liquid tastants or liquid food stimuli confirmed that the insula is involved in processing all three dimensions of taste. More experimental studies are required to investigate whether brain activations differ between liquid tastants and food. The coordinates of activated brain areas and brain maps are provided to serve as references for future taste/food studies.



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Contrasting functional imaging parametric maps: The mislocation problem and alternative solutions

Publication date: 1 April 2018
Source:NeuroImage, Volume 169
Author(s): Mathieu Bourguignon, Nicola Molinaro, Vincent Wens
In the field of neuroimaging, researchers often resort to contrasting parametric maps to identify differences between conditions or populations. Unfortunately, contrast patterns mix effects related to amplitude and location differences and tend to peak away from sources of genuine brain activity to an extent that scales with the smoothness of the maps. Here, we illustrate this mislocation problem on source maps reconstructed from magnetoencephalographic recordings and propose a novel, dedicated location-comparison method. In realistic simulations, contrast mislocation was on average ∼10 mm when genuine sources were placed at the same location, and was still above 5 mm when sources were 20 mm apart. The dedicated location-comparison method achieved a sensitivity of ∼90% when inter-source distance was 12 mm. Its benefit is also illustrated on real brain-speech entrainment data. In conclusion, contrasts of parametric maps provide precarious information for source location. To specifically address the question of location difference, one should turn to dedicated methods as the one proposed here.



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Early use of 80 Hz subthalamic stimulation in Parkinson's disease as an alternative for High-frequency stimulation induced gait changes and postural instability

Publication date: Available online 20 December 2017
Source:Brain Stimulation
Author(s): Marcelo D. Mendonça, Raquel Barbosa, Alexandra Seromenho-Santos, Carla Reizinho, Paulo Bugalho




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Vestibulo-cochlear function in inflammatory neuropathies

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Marisa Blanquet, Jens A. Petersen, Antonella Palla, Dorothe Veraguth, Konrad P. Weber, Dominik Straumann, Alexander A. Tarnutzer, Hans H. Jung
ObjectiveWe aimed to quantify peripheral-vestibular deficits that may contribute to imbalanced stance/gait in patients with inflammatory neuropathies.MethodsTwenty-one patients (58±15y [mean age±1SD]; chronic-inflammatory-demyelinating-polyneuropathy=10, Guillain-Barré Syndrome=5, Anti-MAG peripheral neuropathy=2, multifocal-motor-neuropathy=4) were compared with 26 healthy controls. All subjects received video-head-impulse testing (vHIT), caloric irrigation and cervical/ocular vestibular-evoked myogenic-potentials (VEMPs). The Yardley vertigo-symptom-scale (VSS) was used to assess vertigo/dizziness. Postural stability was assessed using the functional gait-assessment (FGA). Pure-tone audiograms (n=18), otoacoustic emissions (n=12) and auditory brainstem responses were obtained (n=12).ResultsSemicircular-canal hypofunction was noted in 9/21 (43%) patients (vHIT=6; caloric irrigation=5), whereas otolith function was impaired in 12/21 (57%) (oVEMPs=8; cVEMPs=5), resulting in vestibular impairment of at least one sensor in 13/21 (62%). On average, 2.4±1.1 vestibular end organs (each side: anterior/posterior/horizontal canal, utriculus, sacculus; total=10) were affected. The VSS-scores were higher in patients (16.8±8.6 vs. 9.5±6.2, p=0.002) but did not correlate with the number of affected organs. Auditory neuropathy was found in 1/12 (8%) patients.ConclusionImpairment of one or more vestibular end organs was frequent, but usually mild, possibly contributing to imbalance of stance/gait in inflammatory neuropathies.SignificanceWhile our data does not support routine vestibular testing in inflammatory neuropathies, this may be considered in selected cases.



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Spectral and temporal electroencephalography measures reveal distinct neural networks for the acquisition, consolidation, and interlimb transfer of motor skills in healthy young adults

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): M.P. Veldman, N.M. Maurits, M.A.M. Nijland, N.E. Wolters, J.C. Mizelle, T. Hortobágyi
ObjectivePlasticity of the central nervous system likely underlies motor learning. It is however unclear, whether plasticity in cortical motor networks is motor learning stage-, activity-, or connectivity-dependent.MethodsFrom electroencephalography (EEG) data, we quantified effective connectivity by the phase slope index (PSI), neuronal activity by event-related desynchronization, and sensorimotor integration by N30 during the stages of visuomotor skill acquisition, consolidation, and interlimb transfer.ResultsAlthough N30 amplitudes and event-related desynchronization in parietal electrodes increased with skill acquisition, changes in PSI correlated most with motor performance in all stages of motor learning. Specifically, changes in PSI between the premotor, supplementary motor, and primary motor cortex (M1) electrodes correlated with skill acquisition, whereas changes in PSI between electrodes representing M1 and the parietal and primary sensory cortex (S1) correlated with skill consolidation. The magnitude of consolidated interlimb transfer correlated with PSI between bilateral M1s and between S1 and M1 in the non-practiced hemisphere.ConclusionsSpectral and temporal EEG measures but especially PSI correlated with improvements in complex motor behavior and revealed distinct neural networks in the acquisition, consolidation, and interlimb transfer of motor skills.SignificanceA complete understanding of the neuronal mechanisms underlying motor learning can contribute to optimizing rehabilitation protocols



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Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals

Publication date: Available online 20 December 2017
Source:Clinical Neurophysiology
Author(s): Claudio Babiloni, Giuseppe Noce, Alfredo Pennica, Paolo Onorati, Paolo Capotosto, Claudio Del Percio, Paolo Roma, Valentina Correr, Elisa Piccinni, Ginevra Toma, Andrea Soricelli, Francesco Di Campli, Laura Gianserra, Lorenzo Ciullini, Antonio Aceti, Elisabetta Teti, Loredana Sarmati, Gloria Crocetti, Raffaele Ferri, Valentina Catania, Maria Teresa Pascarelli, Massimo Andreoni, Stefano Ferracuti
ObjectiveHere we evaluated the hypothesis that resting state electroencephalographic (EEG) cortical sources correlated with cognitive functions and discriminated asymptomatic treatment-naïve HIV subjects (no AIDS).MethodsEEG, clinical, and neuropsychological data were collected in 103 treatment-naïve HIV subjects (88 males; mean age 39.8 years ± 1.1 standard error of the mean, SE). An age-matched group of 70 cognitively normal and HIV-negative (Healthy; 56 males; 39.0 years ± 2.0 SE) subjects, selected from a local university archive, was used for control purposes. LORETA freeware was used for EEG source estimation in fronto-central, temporal, and parieto-occipital regions of interest.ResultsWidespread sources of delta (< 4 Hz) and alpha (8-12 Hz) rhythms were abnormal in the treatment-naïve HIV group. Fronto-central delta source activity showed a slight but significant (p < 0.05, corrected) negative correlation with verbal and semantic test scores. So did parieto-occipital delta/alpha source ratio with memory and composite cognitive scores. These sources allowed a moderate classification accuracy between HIV and control individuals (area under the ROC curves of 70-75%).ConclusionsRegional EEG abnormalities in quiet wakefulness characterized treatment-naïve HIV subjects at the individual level.SignificanceThis EEG approach may contribute to the management of treatment-naïve HIV subjects at risk of cognitive deficits.



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Rattle-type Au@Cu2−xS hollow mesoporous nanocrystals with enhanced photothermal efficiency for intracellular oncogenic microRNA detection and chemo-photothermal therapy

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Yu Cao, Shuzhou Li, Chao Chen, Dongdong Wang, Tingting Wu, Haifeng Dong, Xueji Zhang
The coupling of the localized surface plasma resonance (LSPR) between noble metals of Au, Ag and Cu and semiconductors of Cu2−xE (E = S, Se, Te) opens new regime to design photothermal (PT) agents with enhanced PT conversion efficiency. However, it is rarely explored on fabricating of engineered dual plasmonic hybrid nanosystem for combinatory therapeutic-diagnostic applications. Herein, rattle-type Au@Cu2−xS hollow mesoporous nanoparitcles with advanced PT conversion efficiency are designed for cellular vehicles and chemo-photothermal synergistic therapy platform. The LSPR coupling between the Au core and Cu2−xS shell are investigated experimentally and theoretically to generate a PT conversion efficiency high to 35.2% and enhanced by 11.3% than that of Cu2−xS. By conjugating microRNA (miRNA) gene probe on the surface, it can realize the intracellular oncogenic miRNA detection. After loading of anticancer drug doxorubicin into the cavity of the Au@Cu2−xS, the antitumor therapy efficacy is greatly enhanced in vitro and in vivo due to the NIR photoactivation chemo- and photothermal synergistic therapy. The rattle-type metal-semiconductor hollow mesoporous nanostructure with efficient LSPR coupling and high cargo loading capability will be beneficial to future design of LSPR-based photothermal agents for a broad range of biomedical application.



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Microenvironments to study migration and somal translocation in cortical neurons

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Shifang Zhao, Wenqiang Fan, Xiang Guo, Longjian Xue, Benedikt Berninger, Marcelo J. Salierno, Aránzazu del Campo
Migrating post-mitotic neurons of the developing cerebral cortex undergo terminal somal translocation (ST) when they reach their final destination in the cortical plate. This process is crucial for proper cortical layering and its perturbation can lead to brain dysfunction. Here we present a reductionist biomaterials platform that faithfully supports and controls the distinct phases of terminal ST in vitro. We developed microenvironments with different adhesive molecules to support neuronal attachment, neurite extension, and migration in distinct manners. Efficient ST occurred when the leading process of migratory neurons crossed from low-to high-adhesive areas on a substrate, promoting spreading of the leading growth cone. Our results indicate that elementary adhesive cell-substrate interactions strongly influence migratory behavior and the final positioning of neurons during their developmental journey. This in vitro model allows advanced experimentation to reveal the microenvironmental requirements underlying cortical layer development and disorders.



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Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Marta Overchuk, Gang Zheng
Despite rapid advancements in the field of nanotechnology, there is mounting frustration in the scientific community regarding the translational impact of nanomedicine. Modest therapeutic performance of FDA-approved nanomedicines combined with multiple disappointing clinical trials (such as phase III HEAT trial) have raised questions about the future of nanomedicine. Encouraging breakthroughs, however, have been made in the last few years towards the development of new classes of nanoparticles that can respond to tumor microenvironmental conditions and successfully deliver therapeutic agents to cancer cells. Concurrently, a great deal of effort has also been devoted to alter various parameters of tumor pathophysiology to pre-treat tumors before nanoparticles are administered. Such 'priming' treatments improve access of the systemically administered agents to the tumor and promote drug penetration into the deeper layers of tumor tissue. This review will highlight recent advances in cancer nanomedicine exploiting both nanoparticle design and tumor microenvironment modification; and provide a critical perspective on the future development of nanomedicine delivery in oncology.

Graphical abstract

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Thrombolytic therapy based on fucoidan-functionalized polymer nanoparticles targeting P-selectin

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Maya Juenet, Rachida Aid-Launais, Bo Li, Alice Berger, Joël Aerts, Véronique Ollivier, Antonino Nicoletti, Didier Letourneur, Cédric Chauvierre
Injection of recombinant tissue plasminogen activator (rt-PA) is the standard drug treatment for thrombolysis. However, rt-PA shows risk of hemorrhages and limited efficiency even at high doses. Polysaccharide-poly(isobutylcyanoacrylate) nanoparticles functionalized with fucoidan and loaded with rt-PA were designed to accumulate on the thrombus. Fucoidan has a nanomolar affinity for the P-selectin expressed by activated platelets in the thrombus. Solid spherical fluorescent nanoparticles with a hydrodynamic diameter of 136 ± 4 nm were synthesized by redox radical emulsion polymerization. The clinical rt-PA formulation was successfully loaded by adsorption on aminated nanoparticles and able to be released in vitro. We validated the in vitro fibrinolytic activity and binding under flow to both recombinant P-selectin and activated platelet aggregates. The thrombolysis efficiency was demonstrated in a mouse model of venous thrombosis by monitoring the platelet density with intravital microscopy. This study supports the hypothesis that fucoidan-nanoparticles improve the rt-PA efficiency. This work establishes the proof-of-concept of fucoidan-based carriers for targeted thrombolysis.

Graphical abstract

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A decade of progress in liver regenerative medicine

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Jingwei Zhang, Xin Zhao, Liguo Liang, Jun Li, Utkan Demirci, ShuQi Wang
Liver diseases can be caused by viral infection, metabolic disorder, alcohol consumption, carcinoma or injury, chronically progressing to end-stage liver disease or rapidly resulting in acute liver failure. In either situation, liver transplantation is most often sought for life saving, which is, however, significantly limited by severe shortage of organ donors. Until now, tremendous multi-disciplinary efforts have been dedicated to liver regenerative medicine, aiming at providing transplantable cells, microtissues, or bioengineered whole liver via tissue engineering, or maintaining partial liver functions via extracorporeal support. In both directions, new compatible biomaterials, stem cell sources, and bioengineering approaches have fast-forwarded liver regenerative medicine towards potential clinical applications. Another important progress in this field is the development of liver-on-a-chip technologies, which enable tissue engineering, disease modeling, and drug testing under biomimetic extracellular conditions. In this review, we aim to highlight the last decade's progress in liver regenerative medicine from liver tissue engineering, bioartificial liver devices (BAL), to liver-on-a-chip platforms, and then to present challenges ahead for further advancement.



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Cold atmospheric plasma (CAP), a novel physicochemical source, induces neural differentiation through cross-talk between the specific RONS cascade and Trk/Ras/ERK signaling pathway

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Ja-Young Jang, Young June Hong, Junsup Lim, Jin Sung Choi, Eun Ha Choi, Seongman Kang, Hyangshuk Rhim
Plasma, formed by ionization of gas molecules or atoms, is the most abundant form of matter and consists of highly reactive physicochemical species. In the physics and chemistry fields, plasma has been extensively studied; however, the exact action mechanisms of plasma on biological systems, including cells and humans, are not well known. Recent evidence suggests that cold atmospheric plasma (CAP), which refers to plasma used in the biomedical field, may regulate diverse cellular processes, including neural differentiation. However, the mechanism by which these physicochemical signals, elicited by reactive oxygen and nitrogen species (RONS), are transmitted to biological system remains elusive. In this study, we elucidated the physicochemical and biological (PCB) connection between the CAP cascade and Trk/Ras/ERK signaling pathway, which resulted in neural differentiation. Excited atomic oxygen in the plasma phase led to the formation of RONS in the PCB network, which then interacted with reactive atoms in the extracellular liquid phase to form nitric oxide (NO). Production of large amounts of superoxide radical (O2⁻) in the mitochondria of cells exposed to CAP demonstrated that extracellular NO induced the reversible inhibition of mitochondrial complex IV. We also demonstrated that cytosolic hydrogen peroxide, formed by O2⁻ dismutation, act as an intracellular messenger to specifically activate the Trk/Ras/ERK signaling pathway. This study is the first to elucidate the mechanism linking physicochemical signals from the CAP cascade to the intracellular neural differentiation signaling pathway, providing physical, chemical and biological insights into the development of therapeutic techniques to treat neurological diseases.



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Editorial Board

Publication date: February 2018
Source:Biomaterials, Volume 156





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Nanoantagonists with nanophase-segregated surfaces for improved cancer immunotherapy

Publication date: February 2018
Source:Biomaterials, Volume 156
Author(s): Yang Ma, Sheng-Lin Qiao, Yi Wang, Yao-Xin Lin, Hong-Wei An, Xiao-Chun Wu, Lei Wang, Hao Wang
The blockade of PD-1/PD-L1 interaction by peptide antagonists can unleash and enhance pre-existing anti-cancer immune responses of T cells to eradicate cancer cells. However, low proteolytic stability is the "Achilles' Heel" of peptides. Here, we first report a nanoantagonist with a physiological temperature sensitive nanophase-segregated surface that exhibits significantly enhanced blood circulation, peptide stability and PD-L1 immune checkpoint blockade efficacy. Thermosensitive polymers with different phase transition temperatures (Tt) are used to form the nanophase-segregated surface on an Au nanorod core. Importantly, the nanophase-segregated surface aids the nanoantagonist to resist protein adsorption and enhance the systemic stability of the linked peptides. Finally, the as-designed nanoantagonist effectively blocks PD-1/PD-L1 interaction in vitro and in vivo, enhances the pre-existing CD8⁺ T cell tumor destruction capability and inhibits tumor growth. This study offers a new strategy for designing nano-formulations for cancer immunotherapy.



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The opportunistic human fungal pathogen Candida albicans promotes the growth and proliferation of commensal Escherichia coli through an iron-responsive pathway

Publication date: Available online 20 December 2017
Source:Microbiological Research
Author(s): Shanshan Li, Xiaoyu Yu, Wenjuan Wu, Daniel Z. Chen, Ming Xiao, Xinhua Huang
Candida albicans is a commensal fungal species that commonly colonizes a heterogeneous mixture of human body where it intimately interacts with other microbes in the host environment such as the gastrointestinal (GI) tract. Most studies in fungal-bacterial interactions are about synergistic or antagonistic effects of bacterial functions on fungal physiological activities including pathogenicity. Very few studies have been demonstrated about the role of fungi on bacteria. In this study, we investigated the interactions between C. albicans and the bacterium Escherichia coli and unexpectedly observed that C. albicans enhances growth and proliferation of Escherichia coli strain K12 by facilitating its cell division. Importantly, we found, based on our genetic screens, that both fungus- and bacterium-derived factors, including the iron-responsive transcription factors Sef1 and Sfu1 in C. albicans and the siderophere enterobactin transporters FepD and FepG in E. coli, actively contribute to this transkingdom interaction. Deletion of SFU1 or SEF1 caused a dramatic reduction in growth enhancement of E. coli. Compared to the wild type E. coli, the enhanced growth of both fepD and fepG null mutants were largely dampened. However, the E. coli mutant lacking entB, a key enzyme catalyzing the biosynthesis of siderophore enterobactin, showed similar growth enhancement as the wild type when co-inoculated with C. albicans. C. albicans promotes growth and proliferation of the commensal bacterium E. coli and an iron-responsive signaling pathway appears to be required. C. albicans may act to supply a siderophere-like molecule that captures the environmental iron to promote the growth of E. coli. Our studies gave insight into a novel interacting mechanism operative in interspecies communication that occurs when bacteria and fungi co-exist.



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Comparative transcriptomic analysis of Cerrena unicolor revealed differential expression of genes engaged in degradation of various kinds of wood

Publication date: Available online 20 December 2017
Source:Microbiological Research
Author(s): Grzegorz Janusz, Andrzej Mazur, Jerzy Wielbo, Piotr Koper, Kamil Żebracki, Anna Pawlik, Beata Ciołek, Andrzej Paszczyński, Agnieszka Kubik-Komar
To explore the number of enzymes engaged by Cerrena unicolor FCL139 for wood degradation, the transcriptomes of the fungus growing on birch, ash, maple sawdust and the control liquid medium were analyzed. Among 12,966 gene models predicted for the C. unicolor genome, 10,396 all-unigenes were detected, of which 9,567 were found to be expressed in each of the tested growth media. The highest number (107) of unique transcripts was detected during fungus growth in the control liquid medium, while the lowest number (11) – in the fungal culture comprising maple saw dust. Analysis of C. unicolor transcriptomes identified numerous genes whose expression differed substantially between the mycelia growing in control medium and each of the sawdust media used, with the highest number (828) of upregulated transcripts observed during the fungus growth on the ash medium. Among the 294 genes that were potentially engaged in wood degradation, the expression of 59 was significantly (p < .01) changed in the tested conditions. The transcripts of 37 of those genes were at least four times more abundant in the cells grown in all sawdust media when compared to the control medium. Upregulated genes coding for cellulases and, to a lower extent, hemicellulases predominated during fungus growth on sawdust. Transcripts encoding cellulolytic enzymes were the most abundant in mycelia grown on birch and maple while lower number of such transcripts was detected in fungus growing on ash. The expression pattern of lignolytic activities-coding genes was strongly dependent on the type of sawdust applied for fungus growth medium.



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Solvent effects on the fluorescence and effective three-photon absorption of a Zn(II)-[meso-tetrakis(4-octyloxyphenyl)porphyrin]

Publication date: June 2018
Source:Optics & Laser Technology, Volume 102
Author(s): Yong Wan, Yuxiong Xue, Ning Sheng, Guanghao Rui, Changgui Lv, Jun He, Bing Gu, Yiping Cui
The fluorescence and effective three-photon absorption (3PA) properties of Zn(II)-[meso-tetrakis(4-octyloxyphenyl)porphyrin] (labeled Zn(II)-porphyrin) dissolved in three different polar solvents were systematically investigated. The electrochemical and photophysical properties of Zn(II)-porphyrin were investigated by ¹H NMR spectra, IR spectra, mass spectroscopy, and electronic absorption spectra. The fluorescence emission of Zn(II)-porphyrin in three different solvents excited at the wavelengths of 420 nm (Soret band) and 550 nm (Q-band) were analyzed. By performing Z-scan experiments with femtosecond laser pulses at a wavelength of 800 nm, the effective 3PA process of Zn(II)-porphyrin in three different solvents was observed and the underlying mechanism was discussed in detail. It is found that the fluorescence spectra slightly depend on the polarity of the solvent. Interestingly, the effective 3PA properties of Zn(II)-porphyrin strongly depend on the solvent polarity. The lower the solvent polarity is, the larger effective 3PA cross-section is. Low polar solvents are beneficial to applications of Zn(II)-porphyrin in optical limiting, photodynamic therapy, etc.



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Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial

Publication date: Available online 20 December 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Lars Norgren, Manesh R. Patel, William R. Hiatt, Daniel M. Wojdyla, F. Gerry R. Fowkes, Iris Baumgartner, Kenneth W. Mahaffey, Jeffrey S. Berger, W. Schuyler Jones, Brian G. Katona, Peter Held, Juuso I. Blomster, Frank W. Rockhold, Martin Björck
ObjectivesCritical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.Design, Materials, MethodsThe EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.ResultsIn EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16–1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13–1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.ConclusionsNearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI.ClinicalTrials.govNCT01732822.



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Reduced methicillin-resistant Staphylococcus aureus biofilm formation in bone cavities by photodynamic therapy

Publication date: Available online 20 December 2017
Source:Photodiagnosis and Photodynamic Therapy
Author(s): Thalita Santos Dantas Araújo, Paôlla Layanna Fernandes Rodrigues, Mariana Sousa Santos, Janeide Muritiba de Oliveira, Luciano Pereira Rosa, Vanderlei Salvador Bagnato, Kate Cristina Blanco, Francine Cristina da Silva
Photodynamic Therapy (PDT) is a promising alternative for the treatment of infectious bone lesions in the oral cavity. The objective of this study was to evaluate the antimicrobial effectiveness of PDT using blue LED associated with curcumin in methicillin-resistant Staphylococcus aureus biofilms (MRSA) in bovine bone cavities by fluorescence spectroscopy. Standardized suspensions of MRSA culture were inoculated into bone lesions to form biofilm. Forty bone species were distributed in three distinct groups: L-C- (control); L + C- (LED for 5 min.); L-C+ (curcumin incubation for 5 min) and L + C+ (PDT). Aliquots of 100 μl were collected from the bone cavities after the treatments and were cultived in BHI for 24 h at 36 °C ± 1 and bacterial colonies counting were performed. Statistical analysis were performed using the paired t-test and analysis of variance (ANOVA) for the variables studied. Results: The control and PDT groups presented statistically significant differences (p< 0.001). It was possible to reduce 3.666 log10 CFU/mL of MRSA and a reduction in the fluorescence emitted after the treatments was observed. The MRSA reduction in biofilms by PDT was the most efficient treatmnent. There was a significant reduction of biofilms in the L + C- and non-PDT groups by fluorescence spectroscopy images.



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Immediate Stress Echocardiography for Low-Risk Chest Pain Patients in the Emergency Department: A Prospective Observational Cohort Study

Publication date: Available online 20 December 2017
Source:The Journal of Emergency Medicine
Author(s): Gregory Jasani, Mia Papas, Avkash J. Patel, Neil Jasani, Brian Levine, Yuanyuan Zhang, Erik S. Marshall
BackgroundEvaluation and disposition of low-risk chest pain (CP) patients in the emergency department (ED) is time consuming and expensive. Low-risk CP often results in hospital admission to rule out myocardial infarction, which leads to additional costs and delays.ObjectiveOur aim was to assess whether an immediate exercise stress echocardiogram (IESE) in the ED will allow safe, efficient, and cost-effective evaluation and discharge of patients with low-risk CP.MethodsLow-risk CP patients (TIMI [Thrombolysis in Myocardial Infarction] score 0–1) presenting to the ED with normal electrocardiogram, no history of coronary artery disease, and negative troponin T received IESE. We followed these patients for major adverse cardiac events and compared them to a control cohort of similar-risk patients admitted with traditional care at 1 and 6 months.ResultsWe enrolled 216 patients, 117 IESE and 109 control. We obtained follow-up at 1 and 6 months in 94% of the IESE group and 88% in the control group. There was no difference in diagnostic catheterization or percutaneous coronary intervention between the 2 groups (6.0% and 1.7% vs. 6.4% and 1.8%; p = 0.89). Median time from triage to discharge was significantly shorter with IESE (572.6 min vs. 1466.0 min), resulting in significantly lower cost ($4380.50 vs. $6191.70). There were no adverse events related to IESE or early discharge.ConclusionsIn our study, IESE for low-risk CP patients presenting to the ED has the potential to be equally safe, more expeditious, and more cost effective than admission to an observation unit.



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D2A-Ala PEPTIDE DERIVED FROM THE UROKINASE RECEPTOR EXERTS ANTI-TUMOURAL EFFECTS IN VITRO AND IN VIVO

Publication date: Available online 19 December 2017
Source:Peptides
Author(s): Federico Furlan, Gabriele Eden, Marco Archinti, Ralitsa Arnaudova, Giuseppina Andreotti, Valentina Citro, Maria Vittoria Cubellis, Andrea Motta, Bernard Degryse
D2A-Ala is a synthetic peptide that has been created by introducing mutations in the original D2A sequence, ¹³⁰IQEGEEGRPKDDR¹⁴² of human urokinase receptor (uPAR). In vitro, D2A-Ala peptide displays strong anti-tumoural properties inhibiting EGF-induced chemotaxis, invasion and proliferation of a human fibrosarcoma cell line, HT 1080, and a human colorectal adenocarcinoma cell line, HT 29. D2A-Ala exerts its effects by preventing EGF receptor (EGFR) phosphorylation.To test D2A-Ala in vivo, this peptide was PEGylated generating polyethyleneglycol (PEG)-D2A-Ala peptide. PEGylation did not alter the inhibitory properties of D2A-Ala. Human tumour xenografts in the immunodeficient nude mice using HT 1080 and HT 29 cell lines showed that PEG-D2A-Ala significantly prevents tumour growth decreasing size, weight and density of tumours. The most efficient doses of the peptide were 5 and 10 mg/kg, thereby relevant for possible development of the peptide into a drug against cancer in particular tumours expressing EGFR.



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Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [18F]-Fluorodeoxyglucose positron emission tomography radiomics features

Publication date: Available online 19 December 2017
Source:Radiotherapy and Oncology
Author(s): Mireia Crispin-Ortuzar, Aditya Apte, Milan Grkovski, Jung Hun Oh, Nancy Y. Lee, Heiko Schöder, John L. Humm, Joseph O. Deasy
Background and purposeHypoxia is a known prognostic factor in head and neck cancer. Hypoxia imaging PET radiotracers such as ¹⁸F-FMISO are promising but not widely available. The aim of this study was therefore to design a surrogate for ¹⁸F-FMISO TBRmax based on ¹⁸F-FDG PET and contrast-enhanced CT radiomics features, and to study its performance in the context of hypoxia-based patient stratification.Methods121 lesions from 75 head and neck cancer patients were used in the analysis. Patients received pre-treatment ¹⁸F-FDG and ¹⁸F-FMISO PET/CT scans. 79 lesions were used to train a cross-validated LASSO regression model based on radiomics features, while the remaining 42 were held out as an internal test subset.ResultsIn the training subset, the highest AUC (0.873±0.008) was obtained from a signature combining CT and ¹⁸F-FDG PET features. The best performance on the unseen test subset was also obtained from the combined signature, with an AUC of 0.833, while the model based on the 90th percentile of ¹⁸F-FDG uptake had a test AUC of 0.756.ConclusionA radiomics signature built from ¹⁸F-FDG PET and contrast-enhanced CT features correlates with ¹⁸F-FMISO TBRmax in head and neck cancer patients, providing significantly better performance with respect to models based on ¹⁸F-FDG PET only. Such a biomarker could potentially be useful to personalize head and neck cancer treatment at centers for which dedicated hypoxia imaging PET radiotracers are unavailable.



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Genotype-driven phase I study of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation for locally advanced rectal cancer

Publication date: Available online 19 December 2017
Source:Radiotherapy and Oncology
Author(s): Ji Zhu, Xinxiang Li, Yunzhu Shen, Yun Guan, Weilie Gu, Peng Lian, Weiqi Sheng, Sanjun Cai, Zhen Zhang
PurposeWe aimed to identify the maximum tolerated dose (MTD) of weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiation according to the UGT1A1∗28 genotype in patients with locally advanced rectal cancer.Patients and methodsPatients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy were screened for the UGT1A1∗28 genotype. Twenty-six patients with either the ∗1∗1 or ∗1∗28 genotype were eligible for dose escalation of irinotecan, and patients with a ∗28∗28 genotype were excluded. The starting dose of weekly irinotecan was 50 mg/m² for the two genotype groups, whereas the dose of capecitabine was fixed at 625 mg/m². Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis (total dose of 50 Gy in 25 fractions).ResultsThe dose of weekly irinotecan was escalated to 95 mg/m² in patients with the ∗1∗1 genotype and to 80 mg/m² in those with the ∗1∗28 genotype. Dose-limiting toxicities (DLTs) were observed in 2/2 ∗1∗1 patients at 95 mg/m² and 2/3 ∗1∗28 patients at 80 mg/m². No DLT cases were observed among the three ∗1∗1 patients at 80 mg/m², and one DLT case was observed among the six patients with ∗1∗28 at 65 mg/m². Hence, 80 mg/m² and 65 mg/m² were the MTDs for the two groups. The most common grade 3 to 4 toxicities were neutropenia and diarrhea.ConclusionA higher dose of weekly irinotecan in combination with capecitabine-based CRT is feasible under the guidance of the UGT1A1∗28 genotype. Further clinical trials at these dose levels are warranted.



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Effect of tooth substrate and porcelain thickness on porcelain veneer failure loads in vitro

Publication date: Available online 19 December 2017
Source:The Journal of Prosthetic Dentistry
Author(s): Chunling Ge, Chad C. Green, Dalene A. Sederstrom, Edward A. McLaren, James A. Chalfant, Shane N. White
Statement of problemBonded porcelain veneers are widely used esthetic restorations. High success and survival rates have been reported, but failures do occur. Fractures are the commonest failure mode. Minimally invasive or thin veneers have gained popularity. Increased enamel and porcelain thickness improve the strength of veneers bonded to enamel, but less is known about dentin or mixed substrates.PurposeThe purpose of this in vitro study was to measure the influences of tooth substrate type (all-enamel, all-dentin, or half-dentin-half-enamel) and veneer thickness on the loads needed to cause initial and catastrophic porcelain veneer failure.Material and methodsModel discoid porcelain veneer specimens of varying thicknesses were bonded to the flattened facial surfaces of incisors with different enamel and dentin tooth substrates, artificially aged, and loaded to failure with a small sphere. Initial and catastrophic fracture events were identified and analyzed statistically and fractographically.ResultsFracture events included initial Hertzian cracks, intermediate radial cracks, and catastrophic gross failure. All specimens retained some porcelain after catastrophic failure. Cement failure occurred at the cement–porcelain interface not at the cement–tooth interface. Porcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or mixed substrates. Increased porcelain thickness substantially raised the loads to catastrophic failure on enamel substrates but only moderately raised the loads to catastrophic failure on dentin or mixed substrates. The veneers bonded to half-dentin-half-enamel behaved remarkably like those bonded wholly to dentin.ConclusionsPorcelain veneers bonded to enamel were substantially stronger and more damage-tolerant than those bonded to dentin or half-enamel-half dentin.



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Long Noncoding RNA in Cancer: Wiring Signaling Circuitry

Publication date: Available online 20 December 2017
Source:Trends in Cell Biology
Author(s): Chunru Lin, Liuqing Yang
Long noncoding RNAs (lncRNAs), which are encoded by a vast less explored region of the human genome, may hold missing drivers of cancer and have gained attention recently as a potentially crucial layer of cancer cell regulation. lncRNAs are aberrantly expressed in a broad spectrum of cancers, and they play key roles in promoting and maintaining tumor initiation and progression, demonstrating their clinical potential as biomarkers and therapeutic targets. Recent discoveries have revealed that lncRNAs act as key signal transduction mediators in cancer signaling pathways by interacting with proteins, RNA, and lipids. Here, we review the mechanisms by which lncRNAs regulate cellular responses to extracellular signals and discuss their clinical potential as diagnostic indicators, stratification markers, and therapeutic targets of combinatorial treatments.



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The visual attention span deficit in Chinese children with reading fluency difficulty

Publication date: February 2018
Source:Research in Developmental Disabilities, Volume 73
Author(s): Jing Zhao, Menglian Liu, Hanlong Liu, Chen Huang
With reading development, some children fail to learn to read fluently. However, reading fluency difficulty (RFD) has not been fully investigated. The present study explored the underlying mechanism of RFD from the aspect of visual attention span. Fourteen Chinese children with RFD and fourteen age-matched normal readers participated. The visual 1-back task was adopted to examine visual attention span. Reaction time and accuracy were recorded, and relevant d-prime (d') scores were computed. Results showed that children with RFD exhibited lower accuracy and lower d' values than the controls did in the visual 1-back task, revealing a visual attention span deficit. Further analyses on d' values revealed that the attention distribution seemed to exhibit an inverted U-shaped pattern without lateralization for normal readers, but a W-shaped pattern with a rightward bias for children with RFD, which was discussed based on between-group variation in reading strategies. Results of the correlation analyses showed that visual attention span was associated with reading fluency at the sentence level for normal readers, but was related to reading fluency at the single-character level for children with RFD. The different patterns in correlations between groups revealed that visual attention span might be affected by the variation in reading strategies. The current findings extend previous data from alphabetic languages to Chinese, a logographic language with a particularly deep orthography, and have implications for reading-dysfluency remediation.



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Amino-Si-rhodamines: A new class of two-photon fluorescent dyes with intrinsic targeting ability for lysosomes

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Hongxing Zhang, Jing Liu, Linfang Wang, Minjia Sun, Xiaohan Yan, Juanjuan Wang, Jian-Ping Guo, Wei Guo
Noninvasive and specific visualization of lysosomes by fluorescence technology is critical for studying lysosomal trafficking in health and disease and for evaluating new cancer therapeutics that target tumor cell lysosomes. To date, there are two basic types of lysosomal probes whose lysosomal localization correlates with lysosomal acidity and endocytosis pathway, respectively. However, the former may suffer from pH-sensitive lysosomal localization and alkalization-induced lysosomal enzyme inactivation, and the latter need long incubation time to penetrate cell membrane due to the energy-dependency of endocytosis process. In this work, a new class of two-photon fluorescent dyes, termed amino-Si-rhodamines (ASiRs), were developed, which possess the intrinsic lysosome-targeted ability that is independent of lysosomal acidity and endocytosis pathway. As a result, ASiRs show not only the stable lysosomal localization against lysosomal pH changes and negligible interference to lysosomal function, but also excellent cell-membrane-permeability due to the energy-independent passive diffusion pathway. These merits, coupled with their excellent two-photon photophysical properties, long-term retention ability in lysosomes, and negligible cytotoxicity, make ASiRs very suitable for real-time and long-term tracking of lysosomes in living cells or tissues without interference to normal cellular processes. Moreover, the easy functionalization via amino linker further allows the construction of various fluorescent probes for biological targets of interest based on ASiR skeleton, as indicated by the cancer-targeted fluorescent probe ASiR6 as well as a fluorescent peroxynitrite probe ASiR-P.

Graphical abstract

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Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy

Publication date: March 2018
Source:Biomaterials, Volume 158
Author(s): Jianhao Lai, Dehua Lu, Chenran Zhang, Hua Zhu, Liquan Gao, Yanpu Wang, Rui Bao, Yang Zhao, Bing Jia, Fan Wang, Zhi Yang, Zhaofei Liu
Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or ⁶⁴Cu, and NIRF and PET imaging using the resulting probes (Dye-αGal-1 and ⁶⁴Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-αGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed in vitro and in vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by ex vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels in vivo; this introduces the possibility of early detection of tumor resistance to therapies.

Graphical abstract

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Zwitterionic starch-based hydrogel for the expansion and “stemness” maintenance of brown adipose derived stem cells

Publication date: March 2018
Source:Biomaterials, Volume 157
Author(s): Dianyu Dong, Tong Hao, Changyong Wang, Ying Zhang, Zhihui Qin, Boguang Yang, Wancai Fang, Lei Ye, Fanglian Yao, Junjie Li
Brown adipose derived stem cells (BADSCs) have become a promising stem cell treatment candidate for myocardial infarction because of their efficiently spontaneous differentiation capacity towards cardiomyocytes. The lack of existing cell passage protocols motivates us to develop a neotype 3D cell expansion technique for BADSCs. In this study, "clickable" zwitterionic starch based hydrogels are developed using methacrylate modified sulfobetaine derived starch with dithiol-functionalized poly (ethylene glycol) as crosslinker via the "thiol-ene" Michael addition reaction. Moreover, CGRGDS peptide is immobilized into the hydrogel via a similar "clickable" approach. Their Young's moduli range from 22.28 to 74.81 kPa depending on the concentration of precursor solutions. Excellent anti-fouling property is also presented owing to the introduction of zwitterionic moieties. BADSCs are homogeneously encapsulated in the hydrogels and then routinely cultured for 10 days. Results suggest a capacious cell proliferation and the extent increases with either the decrease of mechanical strength or the introduction of CGRGDS. More excitingly, the cell "stemness" is well maintained during this period and the expanded cells released from the hydrogels well keep the efficiently spontaneous cardiomyogenic differentiation capacity. Therefore, it is suggested that zwitterionic starch based hydrogel is able for the expansion and "stemness " maintenance of BADSCs.

Graphical abstract

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Utility of Routine Surveillance Imaging for Diffuse Large B-Cell Lymphoma Post Autologous Transplant: A Single Center Experience

Publication date: Available online 19 December 2017
Source:Hematology/Oncology and Stem Cell Therapy
Author(s): Ghulam Rehman Mohyuddin, Ashley Elizabeth Clark, John Roller, Leyla Shune, Tara Lin, Neil Dunavin, Ajoy Dias, Siddhartha Ganguly, Sunil Abhyankar, Joseph McGuirk, Anurag Singh
Surveillance scans after autologous stem cell transplant (auto-HCT) for patients with relapsed/refractory (RR) diffuse large B Cell lymphoma (DLBCL) have no proven survival benefit. We studied survival differences among patients with RR DLBCL post auto-HCT whose recurrences were detected clinically versus with routine surveillance imaging. Among the 139 patients with RR DLBCL that underwent auto-HCT from 2000-2014 at our institution, 37 relapsed: 21 clinical and 16 radiological. The median time to progression was 167 days for the clinical cohort and 565 days for the radiological cohort (p= 0.03), and median overall survival (OS) was 587 days and not reached, respectively (p=0.006). Most patients with relapsed DLBCL after auto-HCT were diagnosed clinically and were likely to be detected earlier and have a shorter OS. Relapse in patients with aggressive disease will likely be detected when clinically apparent, and the outcome of these patients is independent of the way the relapse is diagnosed. Thus, universal scanning after auto-HCT appears to have little benefit.



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What's New Online

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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Use All Forms of Media to Tell Our Story

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1
Author(s): Donna S. Martin




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MyPlate: Meeting Consumers Where They Are, Every Season

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1
Author(s): Brooke Hardison, Angela Leone, Alexandra Day




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Table of Contents

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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Increased Efficacy and Safety of Enteral Nutrition Support with a Protocol (ASNET) in Noncritical Patients: A Randomized Controlled Trial

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1
Author(s): Luis Alfonso Ortíz-Reyes, Lilia Castillo-Martínez, Arianne Itzel Lupián-Angulo, Daniel Dante Yeh, Héctor Isaac Rocha-González, Aurora Elizabeth Serralde-Zúñiga
BackgroundUnintentional underfeeding is common in patients receiving enteral nutrition (EN), and is associated with increased risk of malnutrition complications. Protocols for EN in critically ill patients have been shown to enhance adequacy, resulting in better clinical outcomes; however, outside of intensive care unit (ICU) settings, the influence of a protocol for EN is unknown.ObjectiveTo evaluate the efficacy and safety of implementing an EN protocol in a noncritical setting.DesignRandomized controlled clinical trial.Participants and settingsThis trial was conducted from 2014 to 2016 in 90 adult hospitalized patients (non-ICU) receiving exclusively EN. Patients with carcinomatosis, ICU admission, or <72 hours of EN were excluded.InterventionThe intervention group received EN according to a protocol, whereas the control group was fed according to standard practice.Main outcome measuresThe proportion of patients receiving ≥80% of their caloric target at Day 4 after EN initiation.Statistical analyses performedStudent t test or Wilcoxon rank-sum test were used for continuous variables and the difference between the groups in the time to receipt of the optimal amount of nutrition was analyzed using Kaplan-Meier curves.ResultsForty-five patients were randomized to each group. At Day 4 after EN initiation, 61% of patients in the intervention arm had achieved the primary end point compared with 23% in the control group (P=0.001). In malnourished patients, 63% achieved the primary end point in the intervention group compared with 16% in the control group (P=0.003). The cumulative deficit on Day 4 was lower in the intervention arm compared with the control arm: 2,507 kcal (interquartile range [IQR]=1,262 to 2,908 kcal) vs 3,844 kcal (IQR=2,620 to 4,808 kcal) (P<0.001) and 116 g (IQR=69 to 151 g) vs 191 g (IQR=147 to 244 g) protein (P<0.001), respectively. The rates of gastrointestinal complications were not significantly different between groups.ConclusionsImplementation of an EN protocol outside the ICU significantly improved the delivery of calories and protein when compared with current standard practice without increasing gastrointestinal complications.



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Effectiveness of the Malnutrition Quality Improvement Initiative on Practitioner Malnutrition Knowledge and Screening, Diagnosis, and Timeliness of Malnutrition-Related Care Provided to Older Adults Admitted to a Tertiary Care Facility: A Pilot Study

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1
Author(s): Heidi J. Silver, Kelsey Jones Pratt, Michelle Bruno, Joe Lynch, Kristi Mitchell, Sharon M. McCauley
BackgroundMalnutrition is present in 30% to 50% of hospitalized patients aged 60 years or older. As few as 3.2% of patients identified as high risk have a malnutrition diagnosis documented by medical providers. The Malnutrition Quality Improvement Initiative (MQii) aims to reduce the burden of hospital malnutrition by improving the process and delivery of care.ObjectiveTo evaluate implementing the MQii toolkit of best practice resources for screening, diagnosis, documentation, and timeliness of malnutrition care.DesignThis 6-month prospective pilot included a 3-month intervention with training and education modules tailored to type of practitioner and integrated into existing teaching and clinical workflow.Participants/settingForty-five health care professionals from geriatric, general medicine, and general surgery units at Vanderbilt University Hospital during January to June 2016.Main outcome measuresMalnutrition knowledge by 30-item questionnaire; electronic medical record (EMR) documentation; and timeliness of malnutrition screening, diagnosis, intervention, and discharge planning.Statistical analysesAnalysis of variance was used to test change over time.ResultsMalnutrition knowledge score increased 14%, from 39% to 53% (P=0.009). All patients whose nutrition screen indicated they were malnourished/high risk had registered dietitian nutritionist diagnosis of malnutrition documented in the EMR. The proportion who had medical provider (physician, nurse practitioner, or physician assistant) malnutrition diagnosis documented in the EMR increased 11.6%, from 26.7% to 38.3% (P=0.08). About 95% of malnourished/high risk patients had a documented intervention addressing malnutrition. Inclusion of malnutrition care in the discharge plan increased 4.8%, from 70.0% to 74.8% (P=0.13).ConclusionsThis pilot study demonstrated feasibility of implementing the MQii resources to improve malnutrition knowledge and professionals' skills relevant to screening, diagnosis, intervention, and timeliness of malnutrition care. By optimizing the process and delivery of malnutrition care, it is expected that the quality of clinical care provided to older adults with malnutrition or at high malnutrition risk will improve.



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2018 Call for Abstracts: Posters and Innovations in Practice and Education

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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January 2018 People & Events

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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THE HUDDLESON AWARD 2017: Recognize research excellence—Nominate an article published in the 2017 Journal for the Huddleson

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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January 2018 New in Review

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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January 2018 Sites in Review

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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January 2018 Classified Advertisements

Publication date: January 2018
Source:Journal of the Academy of Nutrition and Dietetics, Volume 118, Issue 1





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Co-Ni-carbon flexible composite fibres for directional magnetic actuation

Publication date: 5 March 2018
Source:Materials & Design, Volume 141
Author(s): Jose Garcia-Torres, Carol Crean, Elisa Vallés
Flexible microcomponents are being widely employed in the microelectronic industry; however; they suffer from a lack of complex movement. To address this problem, we have developed flexible, electrically conductive, magnetic composite fibres showing complex motion in three dimensions with the capacity to be selectively actuated. Flexible carbon-based fibres were prepared by wet-spinning and were subsequently modified by electrodepositing Co-Ni. The high aspect ratio of the fibre (40μm diameter, 3.5cm length) causes a directional dependence in the magnetostatic energy, which will allow for anisotropic actuation of the composite. Thus, the application of magnetic fields allows for a precise control of the movement with high reproducibility and accuracy.

Graphical abstract

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“It's The Disease of Not Listening That I Am Troubled With” – Henry IV

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): William T. Sause




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A letter to my children

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Mordechai Reich




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Radiation Oncology: What's in a name?

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Trevor J. Royce




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Chest wall dose reduction using non-coplanar volumetric modulated arc radiotherapy for lung stereotactic ablative radiotherapy

Publication date: Available online 19 December 2017
Source:Practical Radiation Oncology
Author(s): Amy S. Yu, Peter G Maxim, Billy W Loo, Michael F Gensheimer
PurposeStereotactic ablative radiotherapy (SABR) to lung tumors close to the chest wall can cause rib fractures or chest wall pain. We evaluated and propose a clinically practical solution of using non-coplanar volumetric modulated arc radiotherapy (VMAT) to reduce chest wall dose from lung SABR.Methods and materialsTwenty lung SABR VMAT plans in which the chest wall volume receiving 30Gy or higher (V30) exceeded 30cc were re-planned by non-coplanar VMAT with opposite 15-degree couch kicks. Dosimetric parameters including chest wall V30 and V40, lung V5, V10, V20, and mean dose, Paddick high-dose conformity index, intermediate-dose conformity index, and monitor units (MU) for each plan were used to evaluate the plan quality. The treatment time was also estimated by delivering the entire treatment. Two-sided paired t-test was used to evaluate the difference of the dosimetric parameters between coplanar one arc (cVMAT1), coplanar two arcs (cVMAT2), and non-coplanar two arcs (nVMAT2) plans, and differences with p < 0.05 were considered statistically significant.ResultsV30 and V40 for chest wall were reduced on average by 20%±9% and 15%±11% (mean±SD) from cVMAT2 plans to nVMAT2 plans (p < 0.01 for both comparisons), and 8%±7% and 16%±13% from cVMAT1 plans to cVMAT2 plans (p < 0.003 for both comparisons). The differences in lung mean dose were less than 0.2Gy among cVMAT1, cVMAT2 and nVMAT2. There were no significant differences in lung V5, V10, and V20. On average, the number of MU increased 14% for nVMAT2 compared to cVMAT2. The Paddick high-dose conformity indexes were 0.88±0.03, 0.89±0.04 and 0.91±0.03, and intermediate-dose conformity indexes were 3.88±0.49, 3.80±0.44 and 3.51±0.38 for cVMAT1, cVMAT2 and nVMAT2, respectively.ConclusionsWe found that non-coplanar VMAT plans are feasible, clinically practical to deliver, and significantly reduce V30 and V40 of chest wall without increasing lung dose.



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Mechanochemically induced solid state transformations: The case of raloxifene hydrochloride

Publication date: 1 March 2018
Source:European Journal of Pharmaceutical Sciences, Volume 114
Author(s): Yara Santiago de Oliveira, Alcemira Conceição Oliveira, Alejandro Pedro Ayala
Raloxifene hydrochloride is a benzothiophene derivative mainly used in the prevention and treatment of osteoporosis, but exhibits a low bioavailability hindered by its poor water solubility. In this study, a mechanochemical approach based on neat and liquid-assisted grinding was applied to produce new solid forms of raloxifene hydrochloride. The solids obtained were characterized by several solid-state techniques, such as powder X-ray diffraction, thermal analysis, infrared and Raman spectroscopy. These results showed that depending on the processing conditions solvated or amorphous forms can be produced. The thermal stability of the new forms was also investigated showing that the new forms convert back into the raw material form, as observed by Raman spectroscopy, which was successfully used to discriminate amorphous and crystalline forms, as well as, to monitor in situ the recrystallization process. Furthermore, the solubility of the new forms was evaluated, showing the clear advantage of the amorphous form, when compared with the currently marketed salt.

Graphical abstract

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