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https://www.readbyqxmd.com/read/28336473/unravelling-the-complexities-of-vascular-smooth-muscle-ion-channels-fine-tuning-of-activity-by-ancillary-subunits
#1
REVIEW
Thomas A Jepps
Which ion channel is the most important for regulating vascular tone? Which one is responsible for controlling the resting membrane potential or repolarization? Which channels are recruited by different intracellular signalling pathways or change in certain vascular diseases? Many different ion channels have been identified in the vasculature over the years and claimed as future therapeutic targets. Unfortunately, several of these ion channels are not just found in the vasculature, with many of them also found to have prominent functional roles in different organs of the body, which then leads to off-target effects...
March 20, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28335764/health-care-cost-associated-with-the-use-of-enzyme-inducing-and-non-enzyme-active-antiepileptic-drugs-in-the-uk-a-long-term-retrospective-matched-cohort-study
#2
Simon Borghs, Solène Thieffry, Matthias Noack-Rink, Peter Dedeken, Lai San Hong, Laura Byram, John Logan, Jane Chan, Victor Kiri
BACKGROUND: Some antiepileptic drugs (AEDs) induce expression of hepatic enzymes. This can contribute to comorbidities via interference with metabolic pathways and concomitant drug metabolization, thereby increasing the likelihood of health care interventions. Using medical records, we compared the direct health care cost in patients initiating epilepsy therapy with enzyme-inducing AEDs (EIAEDs) vs non-enzyme-active AEDs (nEAAEDs) over up to 12 years. METHODS: Patients with untreated epilepsy were indexed in the UK Clinical Practice Research Datalink and Hospital Episode Statistics database when prescribed a new EIAED or nEAAED between January 2001 and December 2010...
March 23, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28334377/lrit3-differentially-affects-connectivity-and-synaptic-transmission-of-cones-to-on-and-off-bipolar-cells
#3
Marion Neuillé, Yan Cao, Romain Caplette, Debbie Guerrero-Given, Connon Thomas, Naomi Kamasawa, José-Alain Sahel, Christian P Hamel, Isabelle Audo, Serge Picaud, Kirill A Martemyanov, Christina Zeitz
Purpose: Mutations in LRIT3 lead to complete congenital stationary night blindness (cCSNB). Using a cCSNB mouse model lacking Lrit3 (nob6), we recently have shown that LRIT3 has a role in the correct localization of TRPM1 (transient receptor potential melastatin 1) to the dendritic tips of ON-bipolar cells (BCs), contacting both rod and cone photoreceptors. Furthermore, postsynaptic clustering of other mGluR6 cascade components is selectively eliminated at the dendritic tips of cone ON-BCs...
March 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28332923/different-types-of-pausing-modes-during-transcription-initiation
#4
Eitan Lerner, Antonino Ingargiola, Jookyung J Lee, Sergei Borukhov, Xavier Michalet, Shimon Weiss
In many cases, initiation is rate limiting to transcription. This due in part to the multiple cycles of abortive transcription that delay promoter escape and the transition from initiation to elongation. Pausing of transcription in initiation can further delay promoter escape. The previously hypothesized pausing in initiation was confirmed by two recent studies from Duchi et al. (1) and from Lerner, Chung et al. (2) In both studies, pausing is attributed to lack of forward translocation of the nascent transcript during initiation...
March 23, 2017: Transcription
https://www.readbyqxmd.com/read/28330808/germline-genetic-biomarkers-of-sunitinib-efficacy-in-advanced-renal-cell-carcinoma-results-from-the-renal-effect-trial
#5
Robert J Motzer, Robert A Figlin, Jean-François Martini, Subramanian Hariharan, Neeraj Agarwal, Chun Xiao Li, J Andrew Williams, Thomas E Hutson
BACKGROUND: Sunitinib, the vascular endothelial growth factor pathway inhibitor, is an established standard-of-care for advanced renal cell carcinoma (RCC). This study aimed to assess correlations between candidate germline single nucleotide polymorphisms (SNPs) and sunitinib efficacy in patients from the RENAL EFFECT trial (NCT00267748), a randomized phase II study in patients with metastatic RCC comparing the 4-weeks-on/2-weeks-off schedule and a continuous daily dosing schedule. PATIENTS AND METHODS: Informed consent for pharmacogenetics research was obtained from 202 out of 289 treated patients in the trial...
February 27, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/28327152/trim8-restores-p53-tumour-suppressor-function-by-blunting-n-myc-activity-in-chemo-resistant-tumours
#6
Francesca Mastropasqua, Flaviana Marzano, Alessio Valletti, Italia Aiello, Giuseppe Di Tullio, Annalisa Morgano, Sabino Liuni, Elena Ranieri, Luisa Guerrini, Giuseppe Gasparre, Elisabetta Sbisà, Graziano Pesole, Antonio Moschetta, Mariano Francesco Caratozzolo, Apollonia Tullo
BACKGROUND: TRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway...
March 21, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28326642/neprilysin-inhibition-in-heart-failure-mechanisms-and-substrates-beyond-modulating-natriuretic-peptides
#7
REVIEW
Emilia D'Elia, Attilio Iacovoni, Muthiah Vaduganathan, Ferdinando L Lorini, Stefano Perlini, Michele Senni
The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II...
March 21, 2017: European Journal of Heart Failure
https://www.readbyqxmd.com/read/28325690/one-nuclear-calcium-transient-induced-by-a-single-burst-of-action-potentials-represents-the-minimum-signal-strength-in-activity-dependent-transcription-in-hippocampal-neurons
#8
Yan Yu, Kristin Oberlaender, C Peter Bengtson, Hilmar Bading
Neurons undergo dramatic changes in their gene expression profiles in response to synaptic stimulation. The coupling of neuronal excitation to gene transcription is well studied and is mediated by signaling pathways activated by cytoplasmic and nuclear calcium transients. Despite this, the minimum synaptic activity required to induce gene expression remains unknown. To address this, we used cultured hippocampal neurons and cellular compartment analysis of temporal activity by fluorescence in situ hybridization (catFISH) that allows detection of nascent transcripts in the cell nucleus...
March 6, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28324780/the-longitudinal-relationship-between-control-over-working-hours-and-depressive-symptoms-results-from-slosh-a-population-based-cohort-study
#9
Sophie C Albrecht, Göran Kecklund, Kristiina Rajaleid, Constanze Leineweber
BACKGROUND: Psychosocial work factors can affect depressive moods, but research is inconclusive if flexibility to self-determine working hours (work-time control, WTC) is associated with depressive symptoms over time. We investigated if either sub-dimension of WTC, control over daily hours and control over time off, was related to depressive symptoms over time and examined causal, reversed-causal, and reciprocal pathways. METHODS: The study was based on four waves of the Swedish Longitudinal Occupational Survey of Health which is a follow-up of representative samples of the Swedish working population...
March 7, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28324699/low-vigorous-physical-activity-is-associated-with-increased-adrenocortical-reactivity-to-psychosocial-stress-in-students-with-high-stress-perceptions
#10
Markus Gerber, Sebastian Ludyga, Manuel Mücke, Flora Colledge, Serge Brand, Uwe Pühse
OBJECTIVES: The pathways by which physical activity impacts on participants' health are still not fully understood. The purpose of the present study was to go beyond existing research by combining methods from survey-based and experimental stress research, and by examining whether the potential of vigorous physical activity (VPA) to attenuate physiological and psychological stress responses is moderated by participants' subjective stress perception. METHODS: The sample consisted of 42 undergraduate students (M=21...
March 6, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28322556/can-we-make-small-molecules-lean-optimization-of-a-highly-lipophilic-taro-inhibitor
#11
Mihir Baran Mandal, Zheng Tan, Christina Madsen-Duggan, Alexei V Buevich, John P Caldwell, Reynalda Dejesus, Amy Flattery, Charles G Garlisi, Charles Gill, Sookhee Nicole Ha, Ginny Ho, Sandra Koseoglu, Marc Labroli, Kallol Basu, Sang Ho Lee, Lianzhu Liang, Jenny Liu, Todd W Mayhood, Debra McGuinness, David G McLaren, Xiujuan Wen, Emma R Parmee, Diane Rindgen, Terry Roemer, Payal R Sheth, Paul Tawa, James R Tata, Christine Yang, Shu-Wei Yang, Li Xiao, Hao Wang, Christopher Tan, Haifeng Tang, Paul Walsh, Erika Walsh, Jin Wu, Jing Su
We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO - an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay, and possessed very high lipophilicity (clogP 7.1) with no measureable solubility in PBS buffer. Structure activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28321016/4%C3%AE-8c-inhibits-insulin-secretion-independent-of-ire1%C3%AE-rnase-activity
#12
Hitomi Sato, Yoko Shiba, Yuichi Tsuchiya, Michiko Saito, Kenji Kohno
IRE1α plays an important role in the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the endoplasmic reticulum. 4μ8C, a well-known inhibitor of IRE1α RNase activity, is commonly used to analyze IRE1α function during ER stress in cultured mammalian cells. However, the off-target effects of 4μ8C remain elusive. Pancreatic β-cells synthesize a large amount of insulin in response to high glucose stimulation, and IRE1α plays an important role in insulin secretion from pancreatic β-cells...
March 18, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28320690/use-of-getcheckedonline-a-comprehensive-web-based-testing-service-for-sexually-transmitted-and-blood-borne-infections
#13
Mark Gilbert, Travis Salway, Devon Haag, Christopher K Fairley, Jason Wong, Troy Grennan, Zhaida Uddin, Christopher S Buchner, Tom Wong, Mel Krajden, Mark Tyndall, Jean Shoveller, Gina Ogilvie
BACKGROUND: The British Columbia Centre for Disease Control implemented a comprehensive Web-based testing service GetCheckedOnline (GCO) in September 2014 in Vancouver, Canada. GCO's objectives are to increase testing for sexually transmitted and blood-borne infections (STBBIs), reach high-prevalence populations facing testing barriers, and increase clinical STI service capacity. GCO was promoted through email invitations to provincial STI clinic clients, access codes to clients unable to access immediate clinic-based testing (deferred testers), and a campaign to gay, bisexual, and other men who have sex with men (MSM)...
March 20, 2017: Journal of Medical Internet Research
https://www.readbyqxmd.com/read/28320610/carbon-monoxide-releasing-molecule-401-suppresses-polymorphonuclear-leukocyte-migratory-potential-by-modulating-f-actin-dynamics
#14
Ken Inoue, Eric K Patterson, Alfredo Capretta, Abdel R Lawendy, Douglas D Fraser, Gediminas Cepinskas
Carbon monoxide-releasing molecules (CORMs) suppress inflammation by reducing polymorphonuclear leukocyte (PMN) recruitment to the affected organs. We investigated modulation of PMN-endothelial cell adhesive interactions by water-soluble CORM-401 using an experimental model of endotoxemia in vitro. Human umbilical vein endothelial cells grown on laminar-flow perfusion channels were stimulated with 1 μg/mL lipopolysaccharide for 6 hours and perfused with 100 μmol/L CORM-401 (or inactive compound iCORM-401)-pretreated PMN for 5 minutes in the presence of 1...
March 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28320299/effects-of-seeding-on-lysozyme-amyloid-fibrillation-in-the-presence-of-epigallocatechin-and-polyethylene-glycol
#15
Li-Xiu Kong, Cheng-Ming Zeng
Preformed amyloid fibrils can act as seeds for accelerating protein fibrillation. In the present study, we examined the effects of preformed seeds on lysozyme amyloid fibrillation in the presence of two distinct inhibitors - epigallocatechin (EGC) and polyethylene glycol 2000 (PEG). The results demonstrated that the effects of fibrillar seeds on the acceleration of lysozyme fibrillation depended on the aggregation pathway directed by an inhibitor. EGC inhibited lysozyme fibrillation and modified the peptide chains with quinone moieties in a concentration-dependent manner...
February 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28314838/a-phase-i-study-of-abiraterone-acetate-combined-with-bez235-a-dual-pi3k-mtor-inhibitor-in-metastatic-castration-resistant-prostate-cancer
#16
Xiao X Wei, Andrew C Hsieh, Won Kim, Terence Friedlander, Amy M Lin, Mirela Louttit, Charles J Ryan
LESSONS LEARNED: The combination of standard dose abiraterone acetate and BEZ235, a pan-class I PI3K and mTORC1/2 inhibitor, was poorly tolerated in men with progressive mCRPC.Although the clinical development of BEZ235 has been discontinued in prostate cancer, agents that more selectively target PI3K-AKT-mTOR signaling may have a more favorable therapeutic index and should continue to be explored. BACKGROUND: Androgen receptor (AR) and phosphatidylinositol-3 kinase (PI3K) signaling are two commonly perturbed pathways in prostate cancer...
March 17, 2017: Oncologist
https://www.readbyqxmd.com/read/28304180/nanomedicine-for-the-treatment-of-acute-respiratory-distress-syndrome-the-2016-ats-bear-cage-award-winning-proposal
#17
Jacob S Brenner
After dozens of clinical trials, there are still no FDA-approved drugs which improve mortality in acute respiratory distress syndrome (ARDS). These poor results may in part be caused by three unique pharmacological challenges presented by ARDS: 1) ARDS patients are fragile due to concomitant multiple organ dysfunction, so do not tolerate off-target side effects of drugs; 2) inhaled drug delivery is impeded by the column of proteinaceous fluid covering the injured alveoli; 3) ARDS is heterogeneous in its underlying pathophysiology, so targeting one pathway is unlikely to improve most patients...
March 17, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28303528/human-mass-balance-study-and-metabolite-profiling-of-14-c-niraparib-a-novel-poly-adp-ribose-polymerase-parp-1-and-parp-2-inhibitor-in-patients-with-advanced-cancer
#18
Lotte van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, L Lucas, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen
Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28295344/connectomics-of-synaptic-microcircuits-lessons-from-the-outer-retina
#19
Luke Edward Rogerson, Christian Behrens, Thomas Euler, Philipp Berens, Timm Schubert
Photoreceptors form a sophisticated synaptic complex with bipolar and horizontal cells, transmitting the signals generated by the phototransduction cascade to downstream retinal circuitry. The cone photoreceptor synapse shows several characteristic anatomical connectivity motifs that shape signal transfer: Typically, ON-cone bipolar cells receive photoreceptor input through invaginating synapses; OFF-cone bipolar cells form basal synapses with photoreceptors. Both ON- and OFF-cone bipolar cells are believed to sample from all cone photoreceptors within their dendritic span...
March 10, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28291940/superficial-and-peripheral-dose-in-compensator-based-fff-beam-imrt
#20
Daniel G Zhang, Vladimir Feygelman, Eduardo G Moros, Kujtim Latifi, Sarah Hoffe, Jessica Frakes, Geoffrey G Zhang
Flattening filter-free (FFF) beams produce higher dose rates. Combined with compensator-based intensity modulated radiotherapy (IMRT) techniques, the dose delivery for each beam can be much shorter compared to the flattened beam MLC-based or flattened beam compensator-based IMRT. This 'snap shot' IMRT delivery is beneficial to patients for tumor motion management. Due to softer energy, superficial doses in FFF beam treatment are usually higher than those from flattened beams. Due to no flattening filter, thus less photon scattering, peripheral doses are usually lower in FFF beam treatment...
January 2017: Journal of Applied Clinical Medical Physics
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