Publication date: October 2017
Source:Trends in Endocrinology & Metabolism, Volume 28, Issue 10
Author(s): Lorea Valcarcel-Jimenez, Edoardo Gaude, Veronica Torrano, Christian Frezza, Arkaitz Carracedo
Altered metabolism is a distinct feature of cancer cells. During transformation, the entire metabolic network is rewired to efficiently convert nutrients to biosynthetic precursors to sustain cancer cell growth and proliferation. Whilst the molecular underpinnings of this metabolic reprogramming have been described, its role in tumor progression is still under investigation. Importantly, the mitochondrion is a central actor in many of the metabolic processes that are altered in tumors. Yet, we have only begun to understand the dualities of mitochondrial function during cancer metastasis and therapy resistance. Paradoxically, mitochondrial metabolism can be both advantageous and detrimental to these processes, highlighting the need for a better understanding of the molecular and microenvironmental cues that define the role of this fascinating organelle. In this review article, we present an updated view on the different mitochondrial metabolic strategies adopted by cancer cells to overcome the many hurdles faced during tumor progression.
http://ift.tt/2ypbHXC
Τρίτη 19 Σεπτεμβρίου 2017
Mitochondrial Metabolism: Yin and Yang for Tumor Progression
Editorial Board and Contents
Publication date: October 2017
Source:Trends in Endocrinology & Metabolism, Volume 28, Issue 10
http://ift.tt/2xQDUcN
DNA damage response inhibitors: mechanisms and potential applications in cancer therapy
Source:Cancer Treatment Reviews
Author(s): Laura Carrassa, Giovanna Damia
Over the last decade the unravelling of the molecular mechanisms of the DNA damage response pathways and of the genomic landscape of human tumors have paved the road to new therapeutic approaches in oncology. It is now clear that tumors harbour defects in different DNA damage response steps, mainly signalling and repair, rendering them more dependent on the remaining pathways. We here focus on the proteins ATM, ATR, CHK1 and WEE1, reviewing their roles in the DNA damage response and as targets in cancer therapy. In the last decade specific inhibitors of these proteins have been designed, and their potential antineoplastic activity has been explored both in monotherapy strategies against tumors with specific defects (synthetic lethality approach) and in combination with radiotherapy or chemotherapeutic or molecular targeted agents. The preclinical and clinical evidence of antitumor activity of these inhibitors emanating from these research efforts will be critically reviewed. Lastly, the potential therapeutic feasibility of combining together such inhibitors with the aim to target particular subsets of tumors will be also discussed. .
http://ift.tt/2figrcE
Oral administration of milk-derived phospholipids inhibits penetration of cutaneous nerve fibres into epidermis in a mouse model of acute dry skin
Summary
The density of intraepidermal nerve fibres has been shown to be higher in itchy dry skin than in healthy skin, suggesting that epidermal hyperinnervation is at least partly involved in peripheral itch sensitization. We investigated whether oral administration of milk-derived phospholipids (MPLs) would inhibit epidermal hyperinnervation in a mouse model of dry skin. We found that the number of intraepidermal nerve fibres was significantly lower in the MPL group than in the control group. Expression of nerve growth factor (NGF) levels in the epidermis was significantly decreased by oral administration of MPLs, whereas expression of semaphorin (Sema)3A, a nerve repulsion factor, was increased in the MPL group. These results suggest that dietary MPLs attenuate the penetration of nerve fibres into the epidermis by reducing epidermal NGF levels and increasing Sema3A level. Thus, dietary MPLs may have beneficial effects in the prevention and/or alleviation of dry skin-induced itch by reducing intraepidermal nerve fibre density.
http://ift.tt/2ycNNgR
Plantar keratoderma climatericum: Successful improvement with a topical estriol cream
Summary
Keratoderma climatericum affects menopausal women, and the diagnosis relies on typical clinical findings and exclusion of other potential causes of acquired keratoderma. Although its pathophysiology is still unknown, there has been speculation about its relation to hormonal dysregulation (possibly a local estrogen deficiency) since the 1930s. A female patient with long-lasting keratoderma climatericum was initially prescribed a topical 50% urea ointment and clobetasol propionate 0.05% ointment, with just a slight improvement after 2 months of daily use. The patient was started on topical estriol 0.125 mg/g vaginal cream applied on the plantar surface after her daily shower and application of the same topical 50% urea ointment and clobetasol propionate 0.05% ointment on alternate nights. There was a marked improvement under this regimen with total and fast control of the pruritus. At 6-month follow-up the patient retained total symptomatic control and was just applying the estriol cream and the 50% urea containing ointment. We report a case of a difficult to treat plantar keratoderma that markedly improved after adding a daily topical application of a vaginal cream containing estriol 0.125 mg/g. Trials that determine the efficacy and safety of topical estrogens for keratoderma climatericum are warranted.
http://ift.tt/2ycGmGp
Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke
Source:Journal of Neuroscience Methods
Author(s): Benjamin Okyere, Miranda Creasey, Yeonwoo Lebovitz, Michelle H. Theus
BackgroundLeptomeningeal anastomoses play a critical role in regulating reperfusion following cerebrovascular obstruction; however, methods to evaluate their temporospatial remodeling remains under investigation.New methodWe combined arteriole-specific vessel painting with histological evaluation to assess the density and diameter of inter-collateral vessels between the middle cerebral artery and anterior cerebral artery (MCA-ACA) or posterior cerebral artery (MCA-PCA) in a murine model of permanent middle cerebral artery occlusion (pMCAO).ResultsWhile the overall density was not influenced by pMCAO, the size of MCA-ACA and MCA-PCA vessels had significantly increased 2days post-pMCAO and peaked by 4days compared to the un-injured hemisphere. Using a combination of vessel painting and immunofluorescence, we uniquely observed an induction of cellular division and a remodeling of the smooth muscle cells within the collateral niche following post-pMCAO on whole mount tissue sections. Vessel painting was also applied to pMCAO-injured Cx3cr1GFP mice, in order to identify the spatial relationship between Cx3cr1-positive peripheral-derived monocyte/macrophages and the vessel painted collaterals. Our histological findings were supplemented with analysis of cerebral blood flow using laser Doppler imaging and behavioral changes following pMCAO.Comparison with existing methodsCompared to polyurethane and latex methods for collateral labeling, this new method provides detailed cell-type specific analysis within the collateral niche at the microscopic level, which has previously been unavailable.ConclusionsThis simple and reproducible combination of techniques is the first to dissect the temporospatial remodeling of pial collateral arterioles. The method will advance investigations into the underlying mechanisms governing the intricate processes of arteriogenesis.
http://ift.tt/2xlxZLl
A comparison between the neural correlates of laser and electric pain stimulation and their modulation by expectation
Source:Journal of Neuroscience Methods
Author(s): E.J. Hird, A.K.P. Jones, D. Talmi, W. El-Deredy
BackgroundPain is modulated by expectation. Event-related potential (ERP) studies of the influence of expectation on pain typically utilise laser heat stimulation to provide a controllable nociceptive-specific stimulus. Painful electric stimulation has a number of practical advantages, but is less nociceptive-specific. We compared the modulation of electric versus laser-evoked pain by expectation, and their corresponding pain-evoked and anticipatory ERPs.New MethodWe developed understanding of recognised methods of laser and electric stimulation. We tested whether pain perception and neural activity induced by electric stimulation was modulated by expectation, whether this expectation elicited anticipatory neural correlates, and how these measures compared to those associated with laser stimulation by eliciting cue-evoked expectations of high and low pain in a within-participant design.ResultsDespite sensory and affective differences between laser and electric pain, intensity ratings and pain-evoked potentials were modulated equivalently by expectation, though ERPs only correlated with pain ratings in the laser pain condition. Anticipatory correlates differentiated pain intensity expectation to laser but not electric pain.Comparison with Existing MethodPrevious studies show that laser-evoked potentials are modulated by expectation. We extend this by showing electric pain-evoked potentials are equally modulated by expectation, within the same participants. We also show a difference between the pain types in anticipation.ConclusionsThough laser-evoked potentials express a stronger relationship with pain perception, both laser and electric stimulation may be used to study the modulation of pain-evoked potentials by expectation. Anticipatory-evoked potentials are elicited by both pain types, but they may reflect different processes.
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Spike-contrast: A novel time scale independent and multivariate measure of spike train synchrony
Source:Journal of Neuroscience Methods
Author(s): Manuel Ciba, Takuya Isomura, Yasuhiko Jimbo, Andreas Bahmer, Christiane Thielemann
BackgroundSynchrony within neuronal networks is thought to be a fundamental feature of neuronal networks. In order to quantify synchrony between spike trains, various synchrony measures were developed. Most of them are time scale dependent and thus require the setting of an appropriate time scale. Recently, alternative methods have been developed, such as the time scale independent SPIKE-distance by Kreuz et al..New MethodIn this study, a novel time-scale independent spike train synchrony measure called Spike-contrast is proposed. The algorithm is based on the temporal "contrast" (activity vs. non-activity in certain temporal bins) and not only provides a single synchrony value, but also a synchrony curve as a function of the bin size.ResultsFor most test data sets synchrony values obtained with Spike-contrast are highly correlated with those of the SPIKE-distance (Spearman correlation value of 0.99). Correlation was lower for data containing multiple time scales (Spearman correlation value of 0.89). When analyzing large sets of data, Spike-contrast performed faster.Comparison of existing MethodSpike-contrast is compared to the SPIKE-distance algorithm. The test data consisted of artificial spike trains with various levels of synchrony, including Poisson spike trains and bursts, spike trains from simulated neuronal Izhikevich networks, and bursts made of smaller bursts (sub-bursts).ConclusionsThe high correlation of Spike-contrast with the established SPIKE-distance for most test data, suggests the suitability of the proposed measure. Both measures are complementary as SPIKE-distance provides a synchrony profile over time, whereas Spike-contrast provides a synchrony curve over bin size.
http://ift.tt/2xlPHy0
StimTrack: An open-source software for manual transcranial magnetic stimulation coil positioning
Publication date: Available online 19 September 2017
Source:Journal of Neuroscience Methods
Author(s): Emilia Ambrosini, Simona Ferrante, Mark van de Ruit, Stefano Biguzzi, Vera Colombo, Marco Monticone, Giorgio Ferriero, Alessandra Pedrocchi, Giancarlo Ferrigno, Michael J. Grey
BackgroundDuring Transcranial Magnetic Stimulation (TMS) experiments researchers often use a neuronavigation system to precisely and accurately maintain coil position and orientation.New methodThis study aimed to develop and validate an open-source software for TMS coil navigation. StimTrack uses an optical tracker and an intuitive user interface to facilitate the maintenance of position and orientation of any type of coil within and between sessions. Additionally, online access to navigation data is provided, hereby adding e.g. the ability to start or stop the magnetic stimulator depending on the distance to target or the variation of the orientation angles.ResultsStimTrack allows repeatable repositioning of the coil within 0.7mm for translation and <1° for rotation. Stimulus-response (SR) curves obtained from 19 healthy volunteers were used to demonstrate that StimTrack can be effectively used in a typical experiment. An excellent intra and inter-session reliability (ICC >0.9) was obtained on all parameters computed on SR curves acquired using StimTrack.Comparison with existing methodStimTrack showed a target accuracy similar to that of a commercial neuronavigation system (BrainSight, Rogue Research Inc.). Indeed, small differences both in position (∼0.2mm) and orientation (<1°) were found between the systems. These differences are negligible given the human error involved in landmarks registration.ConclusionsStimTrack, available as supplementary material, is found to be a good alternative for commercial neuronavigation systems facilitating assessment changes in corticospinal excitability using TMS. StimTrack allows researchers to tailor its functionality to their specific needs, providing added value that benefits experimental procedures and improves data quality.
Graphical abstract
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Methane oxidation in lead-contaminated mineral soils under different moisture levels
Abstract
Methane (CH4) oxidation in soil reduces the concentration of this greenhouse gas due to the activity of methanotrophic bacteria. This process is influenced by chemical and physical parameters of soil. We tested the methanotrophic activity of selected mineral soils (Mollic Gleysol, Haplic Podzol, Eutric Cambisol) contaminated with lead (Pb) under different soil water potentials (pF 0; 2.2; 3.2). The heavy metal was added as PbCl2 in two doses. Together with the initial content of Pb in soils, the final contents of heavy metal in different soils were 11.6 and 30.8 mg kg−1 in Eutric Cambisol, 7.1 and 26.3 mg kg−1 in Haplic Podzol, and 12.2 and 31.4 mg kg−1 in Mollic Gleysol (dry mass of the soil is specified in all cases). The results showed relatively low sensitivity of methane oxidation to the addition of the heavy metal. The major factor controlling this process was soil water content, which in most cases turned out to be the most optimal at pF = 2.2.
http://ift.tt/2xw85F9
The sustainable arable land use pattern under the tradeoff of agricultural production, economic development, and ecological protection—an analysis of Dongting Lake basin, China
Abstract
To find a solution regarding sustainable arable land use pattern in the important grain-producing area during the rapid urbanization process, this study combined agricultural production, locational condition, and ecological protection to determine optimal arable land use. Dongting Lake basin, one of the major grain producing areas in China, was chosen as the study area. The analysis of land use transition, the calculation of arable land barycenter, the landscape indices of arable land patches, and the comprehensive evaluation of arable land quality(productivity, economic location, and ecological condition) were adopted in this study. The results showed that (1) in 1990–2000, the arable land increased by 11.77%, and the transformation between arable land and other land use types actively occurred; in 2000–2010, the arable land decreased by 0.71%, and more ecological area (forestland, grassland, and water area) were disturbed and transferred into arable land; (2) urban expansion of the Changsha-Zhuzhou-Xiangtan city cluster (the major economy center of this area) induced the northward movement of the arable land barycenter; (3) the landscape fragmentation and decentralization degree of arable land patches increased during 1990–2010; (4) potential high-quality arable land is located in the zonal area around Dongting Lake, which contains the Li County, Linli County, Jinshi County, Taoyuan County, Taojiang County, Ningxiang County, Xiangxiang County, Shaoshan County, Miluo County, and Zhuzhou County. The inferior low-quality arable land is located in the northwestern Wuling mountainous area, the southeastern hilly area, and the densely populated big cities and their surrounding area. In the optimized arable land use pattern, the high-quality land should be intensively used, and the low-quality arable land should be reduced used or prohibitively used. What is more, it is necessary to quit the arable land away from the surrounding area of cities appropriately, in order to allow more space for urban expansion. This study could provide guidance for sustainable arable land use by both satisfying the future agricultural production and the local economic development, which can be used for the other major grain-producing areas in this rapid developing country.
http://ift.tt/2fhJSf1
Aquatic environmental assessment of Lake Balaton in the light of physical-chemical water parameters
Abstract
One of the issues of the Hungarian Water Management Strategy is the improvement and upgrading of the water of Lake Balaton. The Water Framework Directive (WFD) specifies and sets forth the achievement of the good ecological status. However, the assessment of the water quality of the lake as a complex system requires a comprehensive monitoring and evaluation procedure. Measurements were carried out around the Lake Balaton at ten different locations/sites and 13 physical-chemical parameters were monitored at each measurement site.
For the interpretation of the water chemistry parameters the Aquatic Environmental Assessment (AEA) method devised by authors was used for the water body of the Lake Balaton. The AEA method can be used for all types of the water bodies since it is flexible and using individual weighting procedure for the water chemistry parameters comprehensive information can be obtain. The AEA method was compared with existing EIA methods according to a predefined criterion system and proved to be the most suitable tool for evaluating the environmental impacts in our study.
On the basis of the results it can be concluded that the status of the quality of studied area on the Lake Balaton can be categorized as proper quality (from the outcome of the ten measurement sites this conclusion was reached at seven sites).
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Response of magnetic properties to metal deposition on urban green in Nanjing, China
Abstract
Environmental magnetism is a simple and fast method that can be used to assess heavy metal pollution in urban areas from the relationships between magnetic properties and heavy metal concentrations. Leaves of Osmanthus fragrans, one of the most widely distributed evergreen trees in Nanjing, China, were collected from four different district types, i.e., residential, educational, traffic, and industrial. The magnetic properties and heavy metal concentrations were measured both for unwashed (dust-loaded) and washed leaves. Scanning electron microscopy with energy-dispersive X-ray spectroscopy confirmed that unwashed leaves accumulated much dust due to atmospheric deposition. The value of magnetic properties and heavy metal concentrations in unwashed leaves was significantly higher than those of washed leaves, indicating that these characteristics were mainly derived from atmospheric particulate matter. Saturation isothermal remanent magnetization (SIRM) values obtained from unwashed and washed leaves ranged from 209.14 × 10−6 to 877.85 × 10−6 Am2 kg−1 and from 69.50 × 10−6 to 501.28 × 10−6 Am2 kg−1, respectively. High concentrations of heavy metals, such as Pb and Fe, the Tomlinson pollution load index, and the SIRM of unwashed leaves occurred in the traffic and industrial districts. A preliminary principal component analysis identified the source categories and suggested that industrial activities may be more related to the release of particulate matter rich in Fe. The heavy metal concentrations and pollution load index showed significant positive correlations with the low-frequency magnetic susceptibility and SIRM of unwashed leaves, indicating that these properties can be used to semi-quantify atmospheric heavy metal pollution. Our study suggests that it is possible to employ magnetic measurements as a useful tool for the monitoring and assessment of atmospheric heavy metal pollution.
http://ift.tt/2fipgU7
Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI
Source:Brachytherapy
Author(s): Simon Buus, Maria Lizondo, Steffen Hokland, Susanne Rylander, Erik M. Pedersen, Kari Tanderup, Lise Bentzen
PurposeTo quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration.Methods and MaterialsTwenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTVprostate+3mm. The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy.ResultsNeedle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTVprostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively.ConclusionsSubstantial needle migration in high-dose-rate brachytherapy occurs frequently in 1–3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy.
http://ift.tt/2ycSyXK
Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors
Publication date: Available online 18 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Pervaiz Ali Channar, Aamer Saeed, Fayaz Ali Larik, Muhammad Rafiq, Zaman Ashraf, Farukh Jabeen, Tanzeela Abdul Fattah
The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a–j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a–j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC50 3.17µM while IC50 of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5 µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors.
Graphical abstract
http://ift.tt/2xdCpV5
Potent anti-melanogenic activity and favorable toxicity profile of selected 4-phenyl hydroxycoumarins in the zebrafish model and the computational molecular modeling studies
Publication date: Available online 18 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Jovana B. Veselinović, Aleksandar M. Veselinović, Tatjana Ilic-Tomic, Reeta Davis, Kevin O'Connor, Aleksandar Pavic, Jasmina Nikodinovic-Runic
7-hydroxy-4-phenylcoumarin (7C) and 5,7-dihydroxy-4-phenylcoumarin (5,7C) have been evaluated as potential anti-melanogenic agents in the zebrafish (Danio rerio) model in comparison to commercially utilized depigmenting agents hydroquinone and kojic acid. 7C and 5,7C decreased the body pigmentation at 5 µg/mL, while did not affect the embryos development and survival at doses ≤ 50 µg/mL and ≤ 25 µg/mL. Unlike hydroquinone and kojic acid, 4-phenyl hydroxycoumarins were no melanocytotoxic, showed no cardiotoxic side effects, neither caused neutropenia in zebrafish embryos, suggesting these compounds may present novel skin-whitening agents with improved pharmacological properties. Inhibition of tyrosinase was identified as the possible mode of anti-melanogenic action. Molecular docking studies using the homology model of human tyrosinase as well as adenylate cyclase revealed excellent correlation with experimentally obtained results.
Graphical abstract
http://ift.tt/2xcNZjo
Design, synthesis and biological evaluation of 2-phenylquinoline-4-carboxamide derivatives as a new class of tubulin polymerization inhibitors
Publication date: Available online 18 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Li Zhu, Kaixiu Luo, Ke Li, Yi Jin, Jun Lin
A novel series of 2-phenylquinoline-4-carboxamide derivatives was synthesized, characterized and evaluated for its antiproliferative activity against five cancer cell lines, Hela, SK-OV-3, HCT116, A549 and MDA-MB-468, and a normal human fetal lung fibroblastic cell line, MRC-5. Among them, compound 7b displayed potent cytotoxic activity in vitro against SK-OV-3 and HCT116 cell lines with IC50 values of 0.5 and 0.2 μM, respectively. In general, the antiproliferative activity was correlated with the binding property of the colchicine binding site and inhibitory effect on tubulin polymerization. In addition, immunofluorescence and flow cytometry analysis revealed that selected compounds caused disruption of the mitotic spindle assembly and G2/M phase arrest of the cell cycle, which correlated with proliferation inhibitory activity. Molecular docking analysis demonstrated the interaction of 7b at the colchicine binding site of tubulin. These results indicate these compounds are promising inhibitors of tubulin polymerization for the potent treatment of cancer.
Graphical abstract
http://ift.tt/2xcT5fu
Thioether-stapled macrocyclic inhibitors of the EH domain of EHD1
Publication date: Available online 18 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Alissa J. Kamens, Kaley M. Mientkiewicz, Robyn J. Eisert, Jenna A. Walz, Charles R. Mace, Joshua A. Kritzer
Recycling of receptors from the endosomal recycling compartment to the plasma membrane is a critical cellular process, and recycling is particularly important for maintaining invasiveness in solid tumors. In this work, we continue our efforts to inhibit EHD1, a critical adaptor protein involved in receptor recycling. We applied a diversity-oriented macrocyclization approach to produce cyclic peptides with varied conformations, but that each contain a motif that binds to the EH domain of EHD1. Screening these uncovered several new inhibitors for EHD1's EH domain, the most potent of which bound with a Kd of 3.1 μM. Several of the most potent inhibitors were tested in a cellular assay that measures extent of vesicle recycling. Inhibiting EHD1 could potentially slow cancer invasiveness and metastasis, and these cyclic peptides represent the most potent inhibitors of EHD1 to date.
Graphical abstract
http://ift.tt/2xcSYR6
Synthesis and biological evaluation of novel synthetic chalcone derivatives as anti-tumor agents targeting Cat L and Cat K
Publication date: Available online 17 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yali Wang, Situ Xue, Ruolan Li, Zhihui Zheng, Hong Yi, Zhuorong Li
A series of chalcone derivatives bearing benzamide or benzenesulfonamide moieties were synthesized and evaluated for their anti-tumor effect on HCT116, MCF7 and 143B cell lines in vitro. SAR analysis showed that compounds bearing a benzenesulfonamide group had greater potency than those bearing a benzamide group. It was also shown that compounds with a mono-methyl or mono-halogen group at the 3-position on the terminal phenyl ring were more effective than those with trifluoromethyl or methoxy groups. Compound 8e exhibited the most potent anti-tumor activities against HCT116, MCF7 and 143B cell lines, with IC50 values of 0.597, 0.886 and 0.791 μM, respectively. Molecular docking studies and enzymatic assays demonstrated that the anti-tumor activity of compound 8e might be regulated by Cat L and Cat K.
Graphical abstract
http://ift.tt/2xcSR88
Bifunctional aryliodonium salts for highly efficient radioiodination and astatination of antibodies
Publication date: Available online 19 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): F. Guérard, L. Navarro, Y.-S. Lee, A. Roumesy, C. Alliot, M. Chérel, M.W. Brechbiel, J.-F. Gestin
In this report we describe the development of an alternative approach to arylstannane chemistry for radiolabeling antibodies with radioiodine or astatine based on aryliodonium salts precursors. Bifunctional aryliodonium salts were designed and tested for the synthesis of 125I and 211At labeled prosthetic groups for bioconjugation. The nature of the electron rich aryl group was varied and its impact on the regioselectivity of radiohalogenation was evaluated. Unexpectedly, whereas the 2-thienyl group provided the best regioselectivity towards the radioiodination of the aryl moiety of interest (98:2), it was less selective for astatination (87:13); the anisyl group providing the best regioselectivity in this case (94:6). Under optimized conditions, both radioiodination and astatination could be performed very efficiently in mild conditions (radiochemical yields > 85%). The ionic nature of the precursors was exploited to develop an efficient purification approach: the HPLC step that is usually necessary in conventionnal approaches to optimize removal of organotin toxic precursors and side products was replaced by a filtration through a silica cartridge with a significantly reduced loss of radiolabeled product. The purified radioiodinated and astatinated prosthetic groups were then conjugated efficiently to an anti-CD138 monoclonal antibody (75-80% conjugation yield). By using this novel and simple radiohalogenation procedure, higher overall radiochemical yields of astatination were obtained in comparison with the use of an arylstannane precursor and procedures of the litterature for labeling the same antibody. Overall, due to their simplicity of use and high robustness, these new precursors should simplify the labeling of proteins of interest with iodine and astatine radioisotopes for imaging and therapeutic applications.
Graphical abstract
http://ift.tt/2xcSI4A
New 5-HT1A, 5HT2A and 5HT2C receptor ligands containing a picolinic nucleus: Synthesis, in vitro and in vivo pharmacological evaluation
Publication date: Available online 17 September 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ferdinando Fiorino, Elisa Magli, Ewa Kędzierska, Antonio Ciano, Angela Corvino, Beatrice Severino, Elisa Perissutti, Francesco Frecentese, Paola Di Vaio, Irene Saccone, Angelo A. Izzo, Raffaele Capasso, Paola Massarelli, Ilaria Rossi, Jolanta Orzelska-Gòrka, Jolanta Helena Kotlińska, Vincenzo Santagada, Giuseppe Caliendo
Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki = 0.046 nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki = 0.0224 nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki = 0.8 nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.
Graphical abstract
http://ift.tt/2xdGDfI
Prostate cancer post-prostatectomy radiotherapy: CT vs MRI for vesico-urethral anastomosis target delineation
Source:Radiotherapy and Oncology
Author(s): Daryl Lim Joon, Adeline Lim, Michal Schneider, Chee-Yan Hiew, Nathan Lawrentschuk, Shomik Sengupta, Farshad Foroudi, Trish Jenkins, David Angus, Morikatsu Wada, Michael Chao, Vincent Khoo
BackgroundVesico-urethral anastomosis (VUA) is critical to the clinical target volume (CTV) in post-prostatectomy radiotherapy (PPRT), as it is the commonest site of recurrence. Typically, this is performed on a CT alone but guidelines recommend MRI.ObjectiveTo evaluate the VUA spatial differences between CT (ctVUA) and MRI (mrVUA) and analyse its impact on the CT defined CTV (ctCTV) as recommended by published guidelines.Materials and methodsWe identified 34 patients with a co-registered simulation CT and T2 weighted MRI. The VUA was located on CT and MRI whilst blinded to the opposing scan. The differences were analysed using Wilcoxon's Signed Rank Test. The mrVUA coverage was investigated using three ctCTV margins of 5mm, 8mm and 12mm.ResultsMedian age was 63years with 59% having pT3a disease and median Gleason score of 7. The mrVUA was coincident with the ctVUA in 12% and inferior in 88%. Median difference was 5mm (0–10mm) (P<0.0001). Only a ctCTV margin of 12mm would have encompassed all mrVUAs. A ctCTV margin of 8mm and 5mm resulted in 12% and 38% cases where the VUA was excluded from the ctCTV.ConclusionsMRI is important for the accurate delineation of VUA for PPRT.
http://ift.tt/2jIGLhy
What is the optimal number of library plans in ART for locally advanced cervical cancer?
Source:Radiotherapy and Oncology
Author(s): E. Nováková, S.T. Heijkoop, S. Quint, A.G. Zolnay, J.W.M. Mens, J. Godart, B.J.M. Heijmen, M.S. Hoogeman
PurposeLibrary-of-plans ART is used to manage daily anatomy changes in locally advanced cervical cancer. In our institute, the library contains 2 VMAT plans for patients with large cervix-uterus motion. Increasing this number could be beneficial for tissue sparing, but is burdensome while the dosimetric gain is yet unclear. This study's aim is to determine the optimal number of plans at an individual patient level.Material and methodsData of 14 treated patients were analyzed. Plan libraries were created containing 1–4 VMAT plans. Pre-treatment extent of uterus motion was defined by the 99th percentile of the Hausdorff distance (HD99). For dosimetric evaluations, OARs were contoured in daily CBCT scans, plan selection was simulated, and the V45Gy and V40Gy parameters were recorded.ResultsModerate to strong correlations were found between HD99 and the volume of spared OARs. All patients benefitted from adding a 2nd plan, as is the clinical practice. For patients with a HD99 between 30 and 50mm, a 3-plan library reduced the composite V40Gy with 11–21ml compared to a 2-plan library.ConclusionPatients with large uterus motion (HD99>30mm) would benefit from an extension of the plan library to 3. HD99 is an easy-to-implement criteria to select those patients pre-treatment.
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Heart dose associated with overall survival in locally advanced NSCLC patients treated with hypofractionated chemoradiotherapy
Source:Radiotherapy and Oncology
Author(s): Barbara Stam, Erik van der Bijl, Judi van Diessen, Maddalena M.G. Rossi, Angela Tijhuis, José S.A. Belderbos, Eugène Damen, Jan-Jakob Sonke
Association of heart dose and overall survival was investigated in a cohort including 469 locally-advanced NSCLC patients receiving daily low-dose hypofractionated chemo-radiotherapy. Significant associations were found over a range of dose parameters. Multivariate analysis showed significant associations of heart_V2Gy:HR=1.007%−1 (95% CI:1.002–1.013; p=0.006), age:HR=1.026year−1 (1.011–1.042; p=0.001) and GTV volume:HR=1.001cc−1 (1.000–1.002; p=0.006) with overall survival.
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A pediatric case with peripheral facial nerve palsy caused by a granulomatous lesion associated with cat scratch disease
Source:Brain and Development
Author(s): Chizuko Nakamura, Yuji Inaba, Keiko Tsukahara, Mie Mochizuki, Emi Sawanobori, Yozo Nakazawa, Kouki Aoyama
BackgroundCat scratch disease is a common infectious disorder caused by Bartonella henselae that is transmitted primarily by kittens. It typically exhibits a benign and self-limiting course of subacute regional lymphadenopathy and fever lasting two to eight weeks. The most severe complication of cat scratch disease is involvement of the nervous system, such as encephalitis, meningitis, and polyneuritis. Peripheral facial nerve palsy associated with Bartonella infection is rare; few reported pediatric and adult cases exist and the precise pathogenesis is unknown.Case reportA previously healthy 7-year-old boy presented with fever, cervical lymphadenopathy, and peripheral facial nerve palsy associated with serologically confirmed cat scratch disease. The stapedius muscle reflex was absent on the left side and brain magnetic resonance imaging revealed a mass lesion at the left internal auditory meatus. The patient's symptoms and imaging findings were gradually resolved after the antibiotics and corticosteroids treatment.ConclusionsThe suspected granulomatous lesion was considered to have resulted from the host's immune reaction to Bartonella infection and impaired the facial nerve. This is the first case report providing direct evidence of peripheral facial nerve palsy caused by a suspected granulomatous lesion associated with cat scratch disease and its treatment course.
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CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report
Source:Brain and Development
Author(s): Takuya Hayashida, Yoshiaki Saito, Atsushi Ishii, Hiroyuki Yamada, Ayako Itakura, Toshinori Minato, Tetsuhiro Fukuyama, Yoshihiro Maegaki, Shinichi Hirose
We report a one-year-old boy with early-onset myoclonic epilepsy, developmental arrest, and hyperekplexia during early infancy. He presented with refractory myoclonic/tonic seizures since birth. Electroencephalography revealed multifocal spikes, and rhythmic activities that occurred simultaneous with aggravation of myoclonus accompanied by tonic upper limb elevation. Brain magnetic resonance imaging revealed progressive cerebral atrophy with periventricular signal change and thin corpus callosum at one year of age. A de novo heterozygous missense mutation in the CACNA1A gene was confirmed. This patient was the most severe phenotype of CACNA1A-related early-onset encephalopathy among previous reports.
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Cranial Nerve VII: Facial
ipsilateral peripheral facial nerve paresis or paralysis of unknown etiology. It is generally
self-limited and may be linked to the Herpes simplex virus (HSV) [11]. ...
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conditions our prices arc subject to fluctuation.) Paralysis. Chase. General Paresis. Practical and
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Antibiotic therapy for children with acute otitis media
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Central nervous system involvement in patients with granulomatosis with polyangiitis: a single-center retrospective study
in- volvement of the ear-nose-throat (ENT) system (rhinitis, si- nusitis, mastoiditis, ulcers or
granulomatous inflammation of the nose, subglottic stenosis, destructive bone disease of the ...
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The variation in quality and content of patient‐focused health information on the Internet for otitis media
chondritis, and long‐term hearing problems (Beers & Abramo, 2004; Lee, Kim, &
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Brainstem herniation into the internal acoustic canal secondary to hydrocephalus in context of spontaneous cerebrospinal fluid otorrhea: report of a novel entity
hydrocephalus is secondary to the occlusion of the sinus caused by the mastoiditis [11]. This
would be the first described case in the absence of sigmoid sinus involvement. ...
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L'antibiothérapie pour une otite moyenne aiguë chez l'enfant
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Gliome des Kleinhirns
ab, da der Kontakt von Wachs mit der Schleimhaut der pneumatisierten Zellen zu
einer abakteriellen Mastoiditis führen kann. Die Duraeröffnung ...
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t, fR. CJS. E. 181
Maternity. By & D. S. Greval, Lieutenant-Colonel, IMS 204 StTLPHATHIAZOLE AND ACUTE
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Slowly progressing varicella zoster brainstem encephalitis complicating Ramsay Hunt syndrome in an immunocompetent patient: case report and review of the …
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Medical-Surgical Nursing-E-Book: Concepts for Interprofessional Collaborative Care
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Summary Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an un...
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