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https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#1
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526733/discovery-and-optimization-of-hkt288-a-cadherin-6-targeting-adc-for-the-treatment-of-ovarian-and-renal-cancer
#2
Carl U Bialucha, Scott D Collins, Xiao Li, Parmita Saxena, Xiamei Zhang, Clemens Dürr, Bruno LaFont, Pierric Prieur, Yeonju Shim, Rebecca Mosher, David Lee, Lance Ostrom, Tiancen Hu, Sanela Bilic, Ivana Liric Rajlic, Vladimir Capka, Wei Jiang, Joel P Wagner, GiNell Elliott, Artur Veloso, Jessica C Piel, Meghan M Flaherty, Keith G Mansfield, Emily K Meseck, Tina Rubic-Schneider, Anne Serdakowski London, William R Tschantz, Markus Kurz, Duc Nguyen, Aaron Bourret, Matthew J Meyer, Jason E Faris, Mary J Janatpour, Vivien W Chan, Nicholas C Yoder, Kalli C Catcott, Molly A McShea, Xiuxia Sun, Hui Gao, Juliet Williams, Francesco Hofmann, Jeffrey A Engelman, Seth A Ettenberg, William R Sellers, Emma Lees
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of advanced ovarian and renal cancer patients. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancer. HKT288 is an optimized CDH6-targeting DM4-based antibody drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal anti-tumor activity and highlights CDH6 as a novel antigen for biotherapeutic development...
May 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28526555/modeling-psychomotor-retardation-using-ipscs-from-mct8-deficient-patients-indicates-a-prominent-role-for-the-blood-brain-barrier
#3
Gad D Vatine, Abraham Al-Ahmad, Bianca K Barriga, Soshana Svendsen, Ariel Salim, Leslie Garcia, Veronica J Garcia, Ritchie Ho, Nur Yucer, Tongcheng Qian, Ryan G Lim, Jie Wu, Leslie M Thompson, Weston R Spivia, Zhaohui Chen, Jennifer Van Eyk, Sean P Palecek, Samuel Refetoff, Eric V Shusta, Clive N Svendsen
Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype...
May 8, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28526088/assessment-of-parasitological-findings-in-heartworm-infected-beagles-treated-with-advantage-multi%C3%A2-for-dogs-10-imidacloprid%C3%A2-%C3%A2-2-5-moxidectin-and-doxycycline
#4
Molly D Savadelis, Cameon M Ohmes, Joe A Hostetler, Terry L Settje, Robert Zolynas, Michael T Dzimianski, Andrew R Moorhead
BACKGROUND: Anecdotal reports support the position that the adulticidal heartworm treatment utilizing doxycycline and Advantage Multi®/Advocate® for Dogs (10% imidacloprid + 2.5% moxidectin) has successfully converted antigen-positive dogs to antigen-negative. To date, no controlled experimental studies have demonstrated the adulticidal efficacy of this treatment regimen. The aim of this study was to evaluate the parasitological and clinical efficacy of Advantage Multi® for Dogs (IMD + MOX) and doxycycline in heartworm-infected beagles...
May 19, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28525920/torsade-de-pointes-arrhythmias-arise-at-the-site-of-maximal-heterogeneity-of-repolarization-in-the-chronic-complete-atrioventricular-block-dog
#5
Albert Dunnink, Thom R G Stams, Alexandre Bossu, Veronique M F Meijborg, Jet D M Beekman, Sofieke C Wijers, Jacques M T De Bakker, Marc A Vos
Aims: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. Methods and results: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles...
May 1, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/28524806/racial-and-ethnic-differences-in-treatment-outcomes-among-adults-with-stimulant-use-disorders-after-a-dosed-exercise-intervention
#6
K Sanchez, T L Greer, R Walker, T Carmody, C D Rethorst, M H Trivedi
The current study examined differences in substance abuse treatment outcomes among racial and ethnic groups enrolled in the Stimulant Reduction Intervention using Dosed Exercise (STRIDE) trial, a multisite randomized clinical trial implemented through the National Institute on Drug Abuse's (NIDA's) Clinical Trials Network (CTN). STRIDE aimed to test vigorous exercise as a novel approach to the treatment of stimulant abuse compared to a health education intervention. A hurdle model with a complier average causal effects (CACE) adjustment was used to provide an unbiased estimate of the exercise effect had all participants been adherent to exercise...
May 19, 2017: Journal of Ethnicity in Substance Abuse
https://www.readbyqxmd.com/read/28524260/presence-of-ethanol-sensitive-glycine-receptors-in-medium-spiny-neurons-in-the-mouse-nucleus-accumbens
#7
B Förstera, B Muñoz, M K Lobo, R Chandra, D M Lovinger, L G Aguayo
Alcohol abuse causes major social, economic and health-related problems worldwide. Alcohol, like other drugs of abuse, increases levels of dopamine in the nucleus accumbens, facilitating behavioural reinforcement and substance abuse. Previous studies suggested that glycine receptors (GlyRs) are involved in the regulation of accumbal dopamine levels. Here, we investigated the presence of GlyRs in accumbal dopamine receptor medium spiny neurons (MSNs) of C57BL/6J mice, analyzing mRNA expression-levels and immunoreactivity of GlyR subunits, as well as ethanol sensitivity...
May 19, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28523927/retinoid-bms411-4-5-5-dimethyl-8-phenyl-5-6-dihydronaphthalen-2-yl-carbonyl-amino-benzoic-acid-a-potential-inhibitor-of-ns5a-protein-of-hepatitis-c-virus-a-candidate-for-combined-therapy-of-hepatitis-c-infection
#8
S Ibrahim, M J Asad, R T Mahmood, F H Wattoo, S Akhter, D Shahwar
Hepatitis C infection is a serious health issue worldwide caused by hepatitis C virus (HCV). There is an urgent need of search for new direct acting antiviral drugs due to the rapid development of drug resistance. The HCV NS5A protein is involved in creating resistance against antiviral therapy and there are also many reports that vitamin A deficiency is associated with non-responsiveness to antiviral treatment in HCV infected patients. So the present in silico study was aimed to find the relation between vitamin A deficiency and the NS5A protein's function in antiviral resistance...
2017: Acta Virologica
https://www.readbyqxmd.com/read/28523674/massachusetts-health-reform-s-effect-on-hospitalizations-with-substance-use-disorder-related-diagnoses
#9
Karen E Lasser, Amresh D Hanchate, Danny McCormick, Alexander Y Walley, Richard Saitz, Meng-Yun Lin, Nancy R Kressin
OBJECTIVE: To examine whether Massachusetts (MA) health reform affected substance (alcohol or drug) use disorder (SUD)-related hospitalizations in acute care hospitals. DATA/STUDY SETTING: 2004-2010 MA inpatient discharge data. DESIGN: Difference-in-differences analysis to identify pre- to postreform changes in age- and sex-standardized population-based rates of SUD-related medical and surgical hospitalizations, adjusting for secular trends...
May 19, 2017: Health Services Research
https://www.readbyqxmd.com/read/28522204/peg-interferon-plus-nucleotide-analogue-treatment-versus-no-treatment-in-patients-with-chronic-hepatitis-b-with-a-low-viral-load-a-randomised-controlled-open-label-trial
#10
Annikki de Niet, Louis Jansen, Femke Stelma, Sophie B Willemse, Sjoerd D Kuiken, Sebastiaan Weijer, Carin M J van Nieuwkerk, Hans L Zaaijer, Richard Molenkamp, R Bart Takkenberg, Maarten Koot, Joanne Verheij, Ulrich Beuers, Hendrik W Reesink
BACKGROUND: Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load. METHODS: In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands...
May 15, 2017: Lancet. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28521031/expression-of-host-defense-peptides-in-the-intestine-of-eimeria-challenged-chickens
#11
S Su, D M Dwyer, K B Miska, R H Fetterer, M C Jenkins, E A Wong
Avian coccidiosis is caused by the intracellular protozoan Eimeria, which produces intestinal lesions leading to weight gain depression. Current control methods include vaccination and anticoccidial drugs. An alternative approach involves modulating the immune system. The objective of this study was to profile the expression of host defense peptides such as avian beta-defensins (AvBDs) and liver expressed antimicrobial peptide 2 (LEAP2), which are part of the innate immune system. The mRNA expression of AvBD family members 1, 6, 8, 10, 11, 12, and 13 and LEAP2 was examined in chickens challenged with either E...
May 17, 2017: Poultry Science
https://www.readbyqxmd.com/read/28521004/guidelines-for-the-prevention-and-treatment-of-travelers-diarrhea-a-graded-expert-panel-report
#12
Mark S Riddle, Bradley A Connor, Nicholas J Beeching, Herbert L DuPont, Davidson H Hamer, Phyllis Kozarsky, Michael Libman, Robert Steffen, David Taylor, David R Tribble, Jordi Vila, Philipp Zanger, Charles D Ericsson
Background: : Travelers' diarrhea causes significant morbidity including some sequelae, lost travel time and opportunity cost to both travelers and countries receiving travelers. Effective prevention and treatment are needed to reduce these negative impacts. Methods: : This critical appraisal of the literature and expert consensus guideline development effort asked several key questions related to antibiotic and non-antibiotic prophylaxis and treatment, utility of available diagnostics, impact of multi-drug resistant (MDR) colonization associated with travel and travelers' diarrhea, and how our understanding of the gastrointestinal microbiome should influence current practice and future research...
April 1, 2017: Journal of Travel Medicine
https://www.readbyqxmd.com/read/28518414/systematic-review-of-surgical-and-medical-treatment-for-tertiary-hyperparathyroidism
#13
REVIEW
R R Dulfer, G J H Franssen, D A Hesselink, E J Hoorn, C H J van Eijck, T M van Ginhoven
BACKGROUND: A significant proportion of patients with chronic kidney disease and secondary hyperparathyroidism (HPT) remain hyperparathyroid after kidney transplantation, a state known as tertiary HPT. Without treatment, tertiary HPT can lead to diminished kidney allograft and patient survival. Parathyroidectomy was commonly performed to treat tertiary HPT until the introduction of the calcimimetic drug, cinacalcet. It is not known whether surgery or medical treatment is superior for tertiary HPT...
June 2017: British Journal of Surgery
https://www.readbyqxmd.com/read/28518113/enhanced-sample-multiplexing-of-tissues-using-combined-precursor-isotopic-labeling-and-isobaric-tagging-cpilot
#14
Christina D King, Joseph D Dudenhoeffer, Liqing Gu, Adam R Evans, Renã A S Robinson
There is an increasing demand to analyze many biological samples for disease understanding and biomarker discovery. Quantitative proteomics strategies that allow simultaneous measurement of multiple samples have become widespread and greatly reduce experimental costs and times. Our laboratory developed a technique called combined precursor isotopic labeling and isobaric tagging (cPILOT), which enhances sample multiplexing of traditional isotopic labeling or isobaric tagging approaches. Global cPILOT can be applied to samples originating from cells, tissues, bodily fluids, or whole organisms and gives information on relative protein abundances across different sample conditions...
May 1, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28517366/genie-in-a-blotter-a-comparative-study-of-lsd-and-lsd-analogues-effects-and-user-profile
#15
Leigh D Coney, Larissa J Maier, Jason A Ferris, Adam R Winstock, Monica J Barratt
OBJECTIVE: This study aimed to describe self-reported patterns of use and effects of lysergic acid diethylamide (LSD) analogues (AL-LAD, 1P-LSD, and ETH-LAD) and the characteristics of those who use them. METHODS: An anonymous self-selected online survey of people who use drugs (Global Drug Survey 2016; N = 96,894), which measured perceived drug effects of LSD and its analogues. RESULTS: Most LSD analogue users (91%) had also tried LSD. The proportion of U...
May 18, 2017: Human Psychopharmacology
https://www.readbyqxmd.com/read/28514013/antimicrobial-prescribing-in-dogs-and-cats-in-australia-results-of-the-australasian-infectious-disease-advisory-panel-survey
#16
L Y Hardefeldt, S Holloway, D J Trott, M Shipstone, V R Barrs, R Malik, M Burrows, S Armstrong, G F Browning, M Stevenson
BACKGROUND: Investigations of antimicrobial use in companion animals are limited. With the growing recognition of the need for improved antimicrobial stewardship, there is urgent need for more detailed understanding of the patterns of antimicrobial use in this sector. OBJECTIVES: To investigate antimicrobial use for medical and surgical conditions in dogs and cats by Australian veterinarians. METHODS: A cross-sectional study was performed over 4 months in 2011...
May 17, 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/28513756/divergent-synthesis-of-biflavonoids-yields-novel-inhibitors-of-the-aggregation-of-amyloid-%C3%AE-1-42
#17
Tze Han Sum, Tze Jing Sum, Súil Collins, Warren R J D Galloway, David G Twigg, Florian Hollfelder, David R Spring
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids...
May 17, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28513728/a-droplet-chip-mass-spectrometry-approach-to-study-organic-synthesis-at-nanoliter-scale
#18
R J Beulig, R Warias, J J Heiland, S Ohla, K Zeitler, D Belder
A droplet-based microfluidic device with seamless hyphenation to electrospray mass spectrometry was developed to rapidly investigate organic reactions in segmented flow providing a versatile tool for drug development. A chip-MS interface with an integrated counterelectrode allowed for a flexible positioning of the chip-emitter in front of the MS orifice as well as an independent adjustment of the electrospray potentials. This was necessary to avoid contamination of the mass spectrometer as well as sample overloading due to the high analyte concentrations...
May 17, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28511673/long-term-safety-and-efficacy-of-vismodegib-in-patients-with-advanced-basal-cell-carcinoma-final-update-of-the-pivotal-erivance-bcc-study
#19
Aleksandar Sekulic, Michael R Migden, Nicole Basset-Seguin, Claus Garbe, Anja Gesierich, Christopher D Lao, Chris Miller, Laurent Mortier, Dedee F Murrell, Omid Hamid, Jorge F Quevedo, Jeannie Hou, Edward McKenna, Natalie Dimier, Sarah Williams, Dirk Schadendorf, Axel Hauschild
BACKGROUND: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC...
May 16, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28510297/evaluation-of-the-safety-of-drugs-and-biological-products-used-during-lactation-workshop-summary
#20
REVIEW
J Wang, T Johnson, L Sahin, M S Tassinari, P O Anderson, T E Baker, C Bucci-Rechtweg, G J Burckart, C D Chambers, T W Hale, D Johnson-Lyles, R M Nelson, C Nguyen, D Pica-Branco, Z Ren, H Sachs, J Sauberan, A Zajicek, S Ito, L P Yao
This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies...
June 2017: Clinical Pharmacology and Therapeutics
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