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https://www.readbyqxmd.com/read/28449366/moving-forward-with-the-neuromuscular-junction
#1
REVIEW
Claire Legay, Lin Mei
The neuromuscular junction (NMJ) is indispensable for survival. This synapse between motoneurons and skeletal muscle fibers allows posture, movement and respiration. Therefore, its dysfunction creates pathologies than can be lethal. The molecular mechanisms of NMJ development and maintenance are the subject of intensive studies. This mini-review focuses on some of the most recent discoveries. An unexpected role for a protein, rapsyn, which has been known for 40 years to aggregate acetylcholine receptors has emerged...
April 27, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28449320/a-randomised-double-blind-trial-of-the-safety-and-efficacy-of-omarigliptin-a-once-weekly-dpp-4-inhibitor-in-subjects-with-type-2-diabetes-and-renal-impairment
#2
Antonio Chacra, Ira Gantz, Geraldine Mendizabal, Lucila Durlach, Edward A O'Neill, Zachary Zimmer, Shailaja Suryawanshi, Samuel S Engel, Eseng Lai
AIMS: To assess the safety and efficacy of omarigliptin in subjects with type 2 diabetes mellitus (T2DM) and chronic renal impairment (RI). METHODS: Patients with T2DM with moderate RI (estimated glomerular filtration rate [eGFR] ≥30 to <60 mL/min/1.73 m(2) ) (N=114), severe RI (eGFR <30 mL/min/1.73 m(2) ) (N=55) or end-stage renal disease on dialysis (N=44), who were either not on an antihyperglycaemic agent therapy for at least 12 weeks at screening, washed-off of oral antihyperglycaemic agent monotherapy or low-dose dual combination therapy, or on insulin monotherapy, with baseline glycated haemoglobin (HbA1c) of 6...
April 27, 2017: International Journal of Clinical Practice
https://www.readbyqxmd.com/read/28449218/development-and-pharmacologic-characterization-of-the-rat-6-hz-model-of-partial-seizures
#3
Cameron S Metcalf, Peter J West, Kyle E Thomson, Sharon F Edwards, Misty D Smith, H S White, Karen S Wilcox
OBJECTIVE: The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used preclinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with seizure behaviors similar to those observed in mice including head nod, jaw clonus, and forelimb clonus. METHODS: A convulsive current that elicits these seizure behaviors in 97% of rats (CC97 ) was determined using a Probit analysis...
April 27, 2017: Epilepsia
https://www.readbyqxmd.com/read/28449103/novel-degenerative-and-developmental-defects-in-a-zebrafish-model-of-mucolipidosis-type-iv
#4
Huiqing Li, Wuhong Pei, Sivia Vergarajauregui, Patricia M Zerfas, Nina Raben, Shawn M Burgess, Rosa Puertollano
Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family. In this study we used genome editing to knockout the two mcoln1 genes present in Dario rerio (zebrafish). Our model successfully reproduced the retinal and neuromuscular defects observed in MLIV patients, indicating that this model is suitable for studying the disease pathogenesis...
April 25, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28448781/assessment-of-clinical-pharmacy-interventions-to-reduce-outpatient-use-of-high-risk-medications-in-the-elderly
#5
Sarah C Weddle, A Shaun Rowe, Julie W Jeter, Rachel C Renwick, Shaunta' M Chamberlin, Andrea S Franks
BACKGROUND: Use of high-risk medications in the elderly (HRME) and drug-disease (Rx-DIS) interactions in the elderly, as defined by the Healthcare Effectiveness Data and Information Set (HEDIS) Measures, are significantly associated with mortality, hospital admission, and need for emergency care. No published studies to date evaluate interventions to reduce the use of HEDIS-defined HRME, although many studies have postulated a beneficial effect of such interventions. OBJECTIVE: To evaluate the effect of pharmacist interventions on use of HRME and Rx-DIS interactions in the outpatient elderly population...
May 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/28448670/molecular-mechanisms-underlying-the-filtration-bleb-maintaining-effects-of-suberoylanilide-hydroxamic-acid-saha
#6
Akiko Futakuchi, Toshihiro Inoue, Tomokazu Fujimoto, Utako Kuroda, Miyuki Inoue-Mochita, Eri Takahashi, Saori Ohira, Hidenobu Tanihara
Purpose: Suberoylanilide hydroxamic acid (SAHA) has been shown to support the maintenance of experimental filtration blebs in animal models. This study was performed to investigate the molecular mechanisms underlying the bleb-maintaining effects of SAHA in modulating wound healing activities of conjunctival fibroblasts. Methods: Human conjunctival fibroblasts (HConFs) were pretreated with SAHA before treatment with TGF-β2. Microarray-based screening was used to investigate the gene expression profiles...
April 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28448053/automated-contraction-analysis-of-human-engineered-heart-tissue-for-cardiac-drug-safety-screening
#7
Ingra Mannhardt, Umber Saleem, Anika Benzin, Thomas Schulze, Birgit Klampe, Thomas Eschenhagen, Arne Hansen
Cardiac tissue engineering describes techniques to constitute three dimensional force-generating engineered tissues. For the implementation of these procedures in basic research and preclinical drug development, it is important to develop protocols for automated generation and analysis under standardized conditions. Here, we present a technique to generate engineered heart tissue (EHT) from cardiomyocytes of different species (rat, mouse, human). The technique relies on the assembly of a fibrin-gel containing dissociated cardiomyocytes between elastic polydimethylsiloxane (PDMS) posts in a 24-well format...
April 15, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28448028/system-for-efficacy-and-cytotoxicity-screening-of-inhibitors-targeting-intracellular-mycobacterium-tuberculosis
#8
Xingji Zheng, Yossef Av-Gay
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a leading cause of morbidity and mortality worldwide. With the increased spread of multi drug-resistant TB (MDR-TB), there is a real urgency to develop new therapeutic strategies against M. tuberculosis infections. Traditionally, compounds are evaluated based on their antibacterial activity under in vitro growth conditions in broth; however, results are often misleading for intracellular pathogens like M. tuberculosis since in-broth phenotypic screening conditions are significantly different from the actual disease conditions within the human body...
April 5, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28448014/an-efficient-and-flexible-cell-aggregation-method-for-3d-spheroid-production
#9
Sarah M Maritan, Eric Y Lian, Lois M Mulligan
Monolayer cell culture does not adequately model the in vivo behavior of tissues, which involves complex cell-cell and cell-matrix interactions. Three-dimensional (3D) cell culture techniques are a recent innovation developed to address the shortcomings of adherent cell culture. While several techniques for generating tissue analogues in vitro have been developed, these methods are frequently complex, expensive to establish, require specialized equipment, and are generally limited by compatibility with only certain cell types...
March 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28447490/risks-and-benefits-of-pre-operative-dexmedetomidine-in-oral-and-maxillofacial-surgeries-a-systematic-review
#10
Amin Davoudi, Bijan Movahedian Attar, Elham Shadmehr
Oral and maxillofacial surgeries might induce anxiety and pain to the patients. Sedative agents are one of the best ways for eliminating such consequences. Dexmedetomidine (DEX) is a recent sedative agent which presents higher sedative quality with greater specificity than other drugs. The aim of present paper is to evaluate the risks and benefits of administrating DEX during oral and maxillofacial surgeries by reviewing high quality released articles. Areas covered: Searches on PubMed, Scopus and Web of Science databases were completed with focus on randomized controlled trials (RCT)...
April 27, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28447035/novel-therapeutic-approaches-rett-syndrome-and-human-induced-pluripotent-stem-cell-technology
#11
REVIEW
Mohan Gomathi, Vellingiri Balachandar
Recent advances in induced pluripotent stem cell (iPSC) technology target screening and discovering of therapeutic agents for the possible cure of human diseases. Human induced pluripotent stem cells (hiPSC) are the right kind of platform for testing potency of specific active compounds. Ayurveda, the Indian traditional system of medicine developed between 2,500 and 500 BC, is a science involving the intelligent formulations of herbs and minerals. It can serve as a "goldmine" for novel neuroprotective agents used for centuries to treat neurological disorders...
2017: Stem Cell Investigation
https://www.readbyqxmd.com/read/28446690/antimalarial-efficacy-of-mmv390048-an-inhibitor-of-plasmodium-phosphatidylinositol-4-kinase
#12
Tanya Paquet, Claire Le Manach, Diego González Cabrera, Yassir Younis, Philipp P Henrich, Tara S Abraham, Marcus C S Lee, Rajshekhar Basak, Sonja Ghidelli-Disse, María José Lafuente-Monasterio, Marcus Bantscheff, Andrea Ruecker, Andrew M Blagborough, Sara E Zakutansky, Anne-Marie Zeeman, Karen L White, David M Shackleford, Janne Mannila, Julia Morizzi, Christian Scheurer, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura María Sanz, Francisco Javier Gamo, Janette Reader, Mariette Botha, Koen J Dechering, Robert W Sauerwein, Anchalee Tungtaeng, Pattaraporn Vanachayangkul, Chek Shik Lim, Jeremy Burrows, Michael J Witty, Kennan C Marsh, Christophe Bodenreider, Rosemary Rochford, Suresh M Solapure, María Belén Jiménez-Díaz, Sergio Wittlin, Susan A Charman, Cristina Donini, Brice Campo, Lyn-Marie Birkholtz, Kirsten K Hanson, Gerard Drewes, Clemens H M Kocken, Michael J Delves, Didier Leroy, David A Fidock, David Waterson, Leslie J Street, Kelly Chibale
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model...
April 26, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28446605/crispr-cas9-mediated-gene-knockout-screens-and-target-identification-via-whole-genome-sequencing-uncover-host-genes-required-for-picornavirus-infection
#13
Heon Seok Kim, Kyungjin Lee, Sangsu Bae, Jeongbin Park, Chong-Kyo Lee, Meehyein Kim, Eunji Kim, Minju Kim, Seokjoong Kim, Chonsaeng Kim, Jin-Soo Kim
Several groups have used genome-wide libraries of lentiviruses encoding small-guide RNAs (sgRNAs) for genetic screens. In most cases, sgRNA expression cassettes are integrated into cells by using lentiviruses, and target genes are statistically estimated by the readout of sgRNA sequences after targeted sequencing. We present a new virus-free method for human gene-knockout screens using a genome-wide library of CRISPR/Cas9 sgRNAs based on plasmids, and target gene identification via whole-genome sequencing (WGS) confirming authentic mutations rather than statistical estimating through targeted amplicon sequencing...
April 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28446504/feasibility-of-ultra-high-throughput-functional-screening-of-melanoma-biopsies-for-discovery-of-novel-cancer-drug-combinations
#14
Adam A Friedman, Yun Xia, Lorenzo Trippa, Long P Le, Vivien Igras, Dennie T Frederick, Jennifer A Wargo, Kenneth K Tanabe, Donald P Lawrence, Donna S Neuberg, Keith T Flaherty, David Fisher
Purpose: Successful development of targeted therapy combinations for cancer patients depends on first discovering such combinations in predictive preclinical models. Stable cell lines and mouse xenograft models can have genetic and phenotypic drift and may take too long to generate to be useful as a personalized medicine tool. <p>Experimental Design: To overcome these limitations, we have used a platform of ultra-high-throughput functional screening of primary biopsies preserving both cancer and stroma cell populations from melanoma patients to nominate such novel combinations from a library of  thousands of drug combinations in a patient-specific manner within days of biopsy...
April 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28446463/the-national-cancer-institute-almanac-a-comprehensive-screening-resource-for-the-detection-of-anticancer-drug-pairs-with-enhanced-therapeutic-activity
#15
Susan L Holbeck, Richard Camalier, James A Crowell, Jeevan Prasaad Govindharajulu, Melinda G Hollingshead, Lawrence W Anderson, Eric C Polley, Larry Rubinstein, Apurva K Srivastava, Deborah F Wilsker, Jerry M Collins, James H Doroshow
To date, over 100 small molecule oncology drugs have been approved by the US Food and Drug Administration.  Due to the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations.  Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed.  In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity...
April 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28446445/susceptibility-testing-of-medically-important-parasites
#16
REVIEW
Abebe Genetu Bayih, Anjan Debnath, Edward Mitre, Christopher D Huston, Benoît Laleu, Didier Leroy, Benjamin Blasco, Brice Campo, Timothy N C Wells, Paul A Willis, Peter Sjö, Wesley C Van Voorhis, Dylan R Pillai
In the last 2 decades, renewed attention to neglected tropical diseases (NTDs) has spurred the development of antiparasitic agents, especially in light of emerging drug resistance. The need for new drugs has required in vitro screening methods using parasite culture. Furthermore, clinical laboratories sought to correlate in vitro susceptibility methods with treatment outcomes, most notably with malaria. Parasites with their various life cycles present greater complexity than bacteria, for which standardized susceptibility methods exist...
July 2017: Clinical Microbiology Reviews
https://www.readbyqxmd.com/read/28446260/human-papillomavirus-9-valent-vaccine-for-cancer-prevention-a-systematic-review-of-the-available-evidence
#17
C Signorelli, A Odone, V Ciorba, P Cella, R A Audisio, A Lombardi, L Mariani, F S Mennini, S Pecorelli, G Rezza, G V Zuccotti, A Peracino
In 2014, the Food and Drug Administration approved a new human papillomavirus 9-valent vaccine (9vHPV), targeting nine HPV types: HPV types 6, 11, 16, and 18, which are also targeted by the quadrivalent HPV vaccine (qHPV), plus five additional high cancer risk HPV types (HPV types 31, 33, 45, 52, and 58). The aim of the current study was to systematically retrieve, qualitatively and quantitatively pool, as well as critically appraise all available evidence on 9vHPV from randomized controlled trials (RCTs). We conducted a systematic review of the literature on 9vHPV efficacy, immunogenicity and safety, as well as a systematic search of registered, completed, and ongoing RCTs...
April 27, 2017: Epidemiology and Infection
https://www.readbyqxmd.com/read/28446236/the-malaria-testing-and-treatment-landscape-in-benin
#18
Cyprien Zinsou, Adjibabi Bello Cherifath
BACKGROUND: Since 2004, artemisinin-based combination therapy (ACT) has been the first-line treatment for uncomplicated malaria in Benin. In 2016, a medicine outlet survey was implemented to investigate the availability, price, and market share of anti-malarial treatment and malaria diagnostics. Results provide a timely and important benchmark to measure future interventions aimed at increasing access to quality malaria case management services. METHODS: Between July 5th to August 6th 2016, a cross sectional, nationally-representative malaria outlet survey was conducted in Benin...
April 26, 2017: Malaria Journal
https://www.readbyqxmd.com/read/28445950/the-discovery-of-a-novel-compound-with-potent-antitumor-activity-virtual-screening-synthesis-biological-evaluation-and-preliminary-mechanism-study
#19
Yuanyuan Jin, Linhu Li, Zhaoyong Yang, Mingliang Liu, Huiyuan Guo, Weiyi Shen
Farnesyltransferase has been regarded as a promising drug target against cancer as it is critical for membrane association of several signal transduction proteins. In this study, a novel farnesyltransferase inhibitor (IMB-1406) was identified through virtual screening. It exhibits stronger potency (IC50s: 6.92-8.99 μM) than Sunitinib against all of the tested cancer cell lines. Preliminary studies on mechanism reveal that IMB-1406 induces apoptosis in HepG2 cells by arresting the cell cycle at the S phase, altering anti- and pro-apoptotic proteins leading to mitochondrial dysfunction and activation of caspase-3...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28445553/a-novel-rat-head-gaze-determination-system-based-on-optomotor-responses
#20
Mengbo You, Toshiyuki Yamane, Hiroshi Tomita, Eriko Sugano, Takuya Akashi
The optomotor response of animals is commonly used to measure their visual performance, e.g., rats of different genetically altered strains or various drug tests. With the presentation of stimuli using computer screens or projectors, the common idea focuses on measuring the eye movement or head and/or body movement to characterize changes of the head gaze. However, traditional methods rely on either the invasive fixation of animals, or the judgment of a human observer who reports the stimulus-tracking movements...
2017: PloS One
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