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https://www.readbyqxmd.com/read/28647087/the-evolution-of-library-design-crafting-smart-compound-collections-for-phenotypic-screens
#1
REVIEW
Kerry L Spear, Scott P Brown
The (re)emergence of phenotypic drug discovery has been marked by a growing interest in screening campaigns that utilize phenotypic assays. The key objectives of phenotypic screens are different from those of target-based screens and can require alternate library-design strategies. Designing a library that is appropriate to the selected assay increases the likelihood of identifying better quality hits, which can reduce both timelines and overall cost of the drug-discovery process. Here, we provide an overview of small-molecule library design principles as applied to phenotypic screening...
March 2017: Drug Discovery Today. Technologies
https://www.readbyqxmd.com/read/28640895/the-interplay-of-climate-intervention-and-imported-cases-as-determinants-of-the-2014-dengue-outbreak-in-guangzhou
#2
Qu Cheng, Qinlong Jing, Robert C Spear, John M Marshall, Zhicong Yang, Peng Gong
Dengue is a fast spreading mosquito-borne disease that affects more than half of the population worldwide. An unprecedented outbreak happened in Guangzhou, China in 2014, which contributed 52 percent of all dengue cases that occurred in mainland China between 1990 and 2015. Our previous analysis, based on a deterministic model, concluded that the early timing of the first imported case that triggered local transmission and the excessive rainfall thereafter were the most important determinants of the large final epidemic size in 2014...
June 22, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28634816/critical-biological-parameters-modulate-affinity-as-a-determinant-of-function-in-t-cell-receptor-gene-modified-t-cells
#3
Timothy T Spear, Yuan Wang, Kendra C Foley, David C Murray, Gina M Scurti, Patricia E Simms, Elizabeth Garrett-Mayer, Lance M Hellman, Brian M Baker, Michael I Nishimura
T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity...
June 20, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28631953/a-morpho-phonological-past-tense-processing-as-a-clinical-marker-in-sli-efl-learners
#4
Elena Even-Simkin
The clinical marker in specific language impairment (SLI) population is the subject of considerable debate. SLI is the one of the frequently diagnosed atypical language phenomena found among early school-age children (McArthur et al., 2000; Spear-Swerling, 2006). For example, children with SLI have difficulty applying the Past Tense rule to verbs, even though they can accurately repeat phonologically similar forms of the words (Hoeffner & McClelland, 1993). In this study, I discuss the grammatical deficits in the SLI population by studying the generation of both 'regular' and 'irregular' English Past Tense forms and explain how the rates of the correct use of the 'irregular' versus 'regular' form may be considered as a clinical SLI marker...
February 15, 2017: Clinical Linguistics & Phonetics
https://www.readbyqxmd.com/read/28627133/mesocorticolimbic-hemodynamic-response-in-parkinson-s-disease-patients-with-compulsive-behaviors
#5
Daniel O Claassen, Adam J Stark, Charis A Spears, Kalen J Petersen, Nelleke C van Wouwe, Robert M Kessler, David H Zald, Manus J Donahue
BACKGROUND: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. OBJECTIVES: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors...
June 19, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28624702/evaluation-of-the-antidepressant-therapeutic-potential-of-isocyanine-and-pseudoisocyanine-analogues-of-the-organic-cation-decynium-22
#6
Anwen M Krause-Heuer, Rheaclare Fraser-Spears, Jeremy C Dobrowolski, Mark E Ashford, Naomi A Wyatt, Maxine P Roberts, Georgianna G Gould, Wai-Ching Cheah, Clarissa K L Ng, Mohan Bhadbhade, Bo Zhang, Ivan Greguric, Nial J Wheate, Naresh Kumar, Wouter Koek, Paul D Callaghan, Lynette C Daws, Benjamin H Fraser
Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion...
June 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28619168/comparison-of-asian-porcine-high-fever-disease-isolates-of-porcine-reproductive-and-respiratory-syndrome-virus-to-united-states-isolates-for-their-ability-to-cause-disease-and-secondary-bacterial-infection-in-swine
#7
Susan L Brockmeier, Crystal L Loving, Mitchel V Palmer, Allyn Spear, Tracy L Nicholson, Kay S Faaberg, Kelly M Lager
Epidemiologic data from Asian outbreaks of highly-pathogenic (HP) porcine reproductive and respiratory syndrome virus (PRRSV) suggest that disease severity was associated with both the virulence of the PRRSV isolates and secondary bacterial infections. Previous reports have indicated that U.S. isolates of PRRSV predispose to secondary bacterial infections as well, but the severity of disease that occurred in Asia in pigs infected with these HP-PRRSV strains has not been reported in the U.S. The objectives of this research were to compare the pathogenesis of Asian and U...
May 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/28618489/extortion-provides-alternative-routes-to-the-evolution-of-cooperation-in-structured-populations
#8
Xiongrui Xu, Zhihai Rong, Zhi-Xi Wu, Tao Zhou, Chi Kong Tse
In this paper, we study the evolution of cooperation in structured populations (individuals are located on either a regular lattice or a scale-free network) in the context of repeated games by involving three types of strategies, namely, unconditional cooperation, unconditional defection, and extortion. The strategy updating of the players is ruled by the replicator-like dynamics. We find that extortion strategies can act as catalysts to promote the emergence of cooperation in structured populations via different mechanisms...
May 2017: Physical Review. E
https://www.readbyqxmd.com/read/28602115/total-endovascular-treatment-of-aortic-arch-disease-using-an-arch-endograft-with-3-inner-branches
#9
Rafaëlle Spear, Rachel E Clough, Dominique Fabre, Blayne Roeder, Adrien Hertault, Teresa Martin Gonzalez, Richard Azzaoui, Jonathan Sobocinski, Stéphan Haulon
PURPOSE: To report early experience with a new endovascular graft developed for aortic arch aneurysm repair in patients unfit for open surgery. CASE REPORT: Three consecutive men (62, 74, and 69 years old) at high risk for open repair were treated for postdissection aortic arch aneurysms using a custom-made 3 inner branched endovascular graft. The 2 proximal branches are antegrade and perfuse the innominate artery and the left common carotid artery; the third branch is retrograde and perfuses the left subclavian artery...
June 1, 2017: Journal of Endovascular Therapy
https://www.readbyqxmd.com/read/28599040/intubation-of-the-right-atrium-during-an-attempted-modified-surgical-airway-in-a-pig
#10
Jason Bowman, Andrew Juergens, Matthew McClure, Dave Spear
In modern medicine, the surgical cricothyrotomy is an airway procedure of last resort. In austere environments, however, its simplicity may make it a more feasible option than carrying a full complement of laryngoscopes. To create a Transportation Security Agency-compliant compact first-response bag, we attempted to establish a surgical cricothyrotomy in a pig, using trauma shears, basic medical scissors, a pocket bougie, and an endotracheal tube. Bougies can provide tactile feedback via the "tracheal ring sign" and "stop sign" to indicate positive tracheal placement during orotracheal intubation...
2017: Journal of Special Operations Medicine: a Peer Reviewed Journal for SOF Medical Professionals
https://www.readbyqxmd.com/read/28581371/delayed-presentation-of-cerebral-schistosomiasis-presenting-as-a-tumor-like-brain-lesion
#11
Suradech Suthiphosuwan, Amy Lin, Andrew F Gao, David G Munoz, Julian Spears, Aditya Bharatha
Schistosomiasis is the second most common parasitic infection worldwide. North America is a nonendemic area. However, there are occasional case reports among travelers and immigrants from endemic regions. We describe a case of a 55-year-old Canadian woman who presented with first episode of seizure. Her magnetic resonance imaging scan revealed a mass-like lesion involving the left anterior temporal lobe. The lesion showed T1 hypo- and T2 hyperintense with perilesional brain edema. On post-gadolinium-enhanced T1-weighted sequence, the lesion showed multiple small nodular and linear enhancements, also called an "arborized" appearance...
January 1, 2017: Neuroradiology Journal
https://www.readbyqxmd.com/read/28578639/abiraterone-for-prostate-cancer-not-previously-treated-with-hormone-therapy
#12
Nicholas D James, Johann S de Bono, Melissa R Spears, Noel W Clarke, Malcolm D Mason, David P Dearnaley, Alastair W S Ritchie, Claire L Amos, Clare Gilson, Rob J Jones, David Matheson, Robin Millman, Gerhardt Attard, Simon Chowdhury, William R Cross, Silke Gillessen, Christopher C Parker, J Martin Russell, Dominik R Berthold, Chris Brawley, Fawzi Adab, San Aung, Alison J Birtle, Jo Bowen, Susannah Brock, Prabir Chakraborti, Catherine Ferguson, Joanna Gale, Emma Gray, Mohan Hingorani, Peter J Hoskin, Jason F Lester, Zafar I Malik, Fiona McKinna, Neil McPhail, Julian Money-Kyrle, Joe O'Sullivan, Omi Parikh, Andrew Protheroe, Angus Robinson, Narayanan N Srihari, Carys Thomas, John Wagstaff, James Wylie, Anjali Zarkar, Mahesh K B Parmar, Matthew R Sydes
Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes...
June 3, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28573185/hcv-t-cell-receptor-chain-modifications-to-enhance-expression-pairing-and-antigen-recognition-in-t-cells-for-adoptive-transfer
#13
Kendra C Foley, Timothy T Spear, David C Murray, Kaoru Nagato, Elizabeth Garrett-Mayer, Michael I Nishimura
T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced α and β TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR...
June 16, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28572406/how-an-alloreactive-t-cell-receptor-achieves-peptide-and-mhc-specificity
#14
Yuan Wang, Nishant K Singh, Timothy T Spear, Lance M Hellman, Kurt H Piepenbrink, Rachel H McMahan, Hugo R Rosen, Craig W Vander Kooi, Michael I Nishimura, Brian M Baker
T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease...
June 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28570474/acellular-dermal-matrix-for-the-treatment-and-prevention-of-implant-associated-breast-deformities
#15
Scott L Spear, Mitchel Seruya, Mark W Clemens, Steven Teitelbaum, Maurice Y Nahabedian
No abstract text is available yet for this article.
April 2017: Plastic Surgical Nursing
https://www.readbyqxmd.com/read/28570473/evaluating-long-term-outcomes-following-nipple-sparing-mastectomy-and-reconstruction-in-the-irradiated-breast
#16
Scott L Spear, John Shuck, Lindsay Hannan, Frank Albino, Ketan M Patel
No abstract text is available yet for this article.
April 2017: Plastic Surgical Nursing
https://www.readbyqxmd.com/read/28570467/in-memory-of-dr-scott-spear
#17
Tracey A Hotta
No abstract text is available yet for this article.
April 2017: Plastic Surgical Nursing
https://www.readbyqxmd.com/read/28550117/comparative-exploration-of-multidimensional-flow-cytometry-software-a-model-approach-evaluating-t-cell-polyfunctional-behavior
#18
Timothy T Spear, Michael I Nishimura, Patricia E Simms
Advancement in flow cytometry reagents and instrumentation has allowed for simultaneous analysis of large numbers of lineage/functional immune cell markers. Highly complex datasets generated by polychromatic flow cytometry require proper analytical software to answer investigators' questions. A problem among many investigators and flow cytometry Shared Resource Laboratories (SRLs), including our own, is a lack of access to a flow cytometry-knowledgeable bioinformatics team, making it difficult to learn and choose appropriate analysis tool(s)...
May 26, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28546044/endovascular-repair-of-thoraco-abdominal-and-arch-aneurysms-in-patients-with-connective-tissue-disease-using-branched-and-fenestrated-devices
#19
Rachel E Clough, Teresa Martin-Gonzalez, Katrien Van Calster, Adrien Hertault, Rafaëlle Spear, Richard Azzaoui, Jonathan Sobocinski, Stéphan Haulon
INTRODUCTION: Prophylactic open surgery is the standard practice in patients with connective tissue and thoraco-abdominal (TAAA) and aortic arch disease. Branched and fenestrated devices offer a less invasive alternative but there are concerns regarding the durability of the repair and the effect of the stent graft on the fragile aortic wall. The aim of this study was to evaluate mid-term outcomes of fenestrated and/or branched endografting in patients with connective tissue disease. METHODS: All patients with connective tissue disease that underwent TAAA or arch aneurysm repair using a fenestrated and/or branched endograft in a single high volume centre between 2004 and 2015 were included...
May 22, 2017: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/28511261/current-practice-and-the-future-of-deep-brain-stimulation-therapy-in-parkinson-s-disease
#20
Leonardo Almeida, Wissam Deeb, Chauncey Spears, Enrico Opri, Rene Molina, Daniel Martinez-Ramirez, Aysegul Gunduz, Christopher W Hess, Michael S Okun
Deep brain stimulation (DBS) is an effective therapy for Parkinson's disease patients experiencing motor fluctuations, medication-resistant tremor, and/or dyskinesia. Currently, the subthalamic nucleus and the globus pallidus internus are the two most widely used targets, with individual advantages and disadvantages influencing patient selection. Potential DBS patients are selected using the few existing guidelines and the available DBS literature, and many centers employ an interdisciplinary team review of the individual's risk-benefit profile...
April 2017: Seminars in Neurology
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