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https://www.readbyqxmd.com/read/29494809/disentangling-the-biological-pathways-involved-in-early-features-of-alzheimer-s-disease-in-the-rotterdam-study
#1
Shahzad Ahmad, Christian Bannister, Sven J van der Lee, Dina Vojinovic, Hieab H H Adams, Alfredo Ramirez, Valentina Escott-Price, Rebecca Sims, Emily Baker, Julie Williams, Peter Holmans, Meike W Vernooij, M Arfan Ikram, Najaf Amin, Cornelia M van Duijn
INTRODUCTION: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. METHODS: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume...
February 26, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/29467138/-pathways-patient-centred-decision-counselling-for-women-at-risk-of-cancer-related-infertility-a-protocol-for-a-comparative-effectiveness-cluster-randomised-trial
#2
Terri Lynn Woodard, Aubri S Hoffman, Laura C Crocker, Deborah A Holman, Derek B Hoffman, Jusheng Ma, Roland L Bassett, Viola B Leal, Robert J Volk
INTRODUCTION: National guidelines recommend that all reproductive-age women with cancer be informed of their fertility risks and offered referral to fertility specialists to discuss fertility preservation options. However, reports indicate that only 5% of patients have consultations, and rates of long-term infertility-related distress remain high. Previous studies report several barriers to fertility preservation; however, initial success has been reported using provider education, patient decision aids and navigation support...
February 21, 2018: BMJ Open
https://www.readbyqxmd.com/read/29427304/police-and-mental-health-responses-to-mental-health-crisis-in-the-waikato-region-of-new-zealand
#3
Graham Holman, Anthony John O'Brien, Katey Thom
New Zealand police report a high level of involvement with people in mental health crisis, something that has been reported in the international literature in recent decades. Involvement of police represents a coercive pathway to care and is likely to be associated with use of force. The aim of this study was to investigate the clinical, legal, and social characteristics of individuals subject to police response in the Waikato region of New Zealand. Data were also collected on characteristics of police response, including use of force, time of day, and disposition...
February 10, 2018: International Journal of Mental Health Nursing
https://www.readbyqxmd.com/read/29296755/12-hetre-inhibits-platelet-reactivity-and-thrombosis-in-part-through-the-prostacyclin-receptor
#4
Benjamin E Tourdot, Reheman Adili, Zitha R Isingizwe, Meral Ebrahem, J Cody Freedman, Theodore R Holman, Michael Holinstat
The dihomo-γ-linolenic acid (DGLA)-derived metabolite of 12-lipoxygenase, 12-hydroxy-eicosatrienoic acid (12-HETrE), was recently shown to potently inhibit thrombus formation without prolonging bleeding in murine models. Although 12-HETrE was found to inhibit platelet activation via the Gαs signaling pathway, the Gαs -coupled receptor by which 12-HETrE mediates its antiplatelet effects has yet to be identified. Defining the receptor by which 12-HETrE exerts its effects is key to determining its therapeutic potential as an antiplatelet drug...
June 27, 2017: Blood Advances
https://www.readbyqxmd.com/read/29114841/effect-of-cromakalim-prodrug-1-cklp1-on-aqueous-humor-dynamics-and-feasibility-of-combination-therapy-with-existing-ocular-hypotensive-agents
#5
Uttio Roy Chowdhury, Tommy A Rinkoski, Cindy K Bahler, J Cameron Millar, Jacques A Bertrand, Bradley H Holman, Joseph M Sherwood, Darryl R Overby, Kristen L Stoltz, Peter I Dosa, Michael P Fautsch
Purpose: Cromakalim prodrug 1 (CKLP1) is a water-soluble ATP-sensitive potassium channel opener that has shown ocular hypotensive properties in ex vivo and in vivo experimental models. To determine its mechanism of action, we assessed the effect of CKLP1 on aqueous humor dynamics and in combination therapy with existing ocular hypotensive agents. Methods: Outflow facility was assessed in C57BL/6 mice by ex vivo eye perfusions and by in vivo constant flow infusion following CKLP1 treatment...
November 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29034438/the-pathways-fertility-preservation-decision-aid-website-for-women-with-cancer-development-and-field-testing
#6
Terri L Woodard, Aubri S Hoffman, Laura A Covarrubias, Deborah Holman, Leslie Schover, Andrea Bradford, Derek B Hoffman, Aakrati Mathur, Jerah Thomas, Robert J Volk
PURPOSE: To improve survivors' awareness and knowledge of fertility preservation counseling and treatment options, this study engaged survivors and providers to design, develop, and field-test Pathways: a fertility preservation patient decision aid website for young women with cancer©. METHODS: Using an adapted user-centered design process, our stakeholder advisory group and research team designed and optimized the Pathways patient decision aid website through four iterative cycles of review and revision with clinicians (n = 21) and survivors (n = 14)...
February 2018: Journal of Cancer Survivorship: Research and Practice
https://www.readbyqxmd.com/read/28977442/genetic-modifiers-of-mendelian-disease-huntington-s-disease-and-the-trinucleotide-repeat-disorders
#7
REVIEW
Peter A Holmans, Thomas H Massey, Lesley Jones
In the decades since the genes and mutations associated with the commoner Mendelian disorders were first discovered, technological advances in genetic analysis have made finding genomic variation a much less onerous task. Recently, the global efforts to collect subjects with Mendelian disorders, to better define the disorders and to empower appropriate clinical trials, along with improved genetic technologies, have allowed the identification of genetic variation that does not cause disease, but substantially modifies disease presentation...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28972182/urokinase-type-plasminogen-activator-upa-is-critical-for-progression-of-tuberous-sclerosis-complex-2-tsc2-deficient-tumors
#8
COMPARATIVE STUDY
Victoria Stepanova, Konstantin V Dergilev, Kelci R Holman, Yelena V Parfyonova, Zoya I Tsokolaeva, Mimi Teter, Elena N Atochina-Vasserman, Alla Volgina, Sergei V Zaitsev, Shane P Lewis, Fedor G Zabozlaev, Kseniya Obraztsova, Vera P Krymskaya, Douglas B Cines
Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes ( TSC1 or TSC2 ). LAM is characterized by neoplastic growth of smooth muscle-α-actin-positive cells that destroy lung parenchyma and by the formation of benign renal neoplasms called angiolipomas. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology...
December 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28926528/the-improving-rural-cancer-outcomes-trial-a-cluster-randomised-controlled-trial-of-a-complex-intervention-to-reduce-time-to-diagnosis-in-rural-cancer-patients-in-western-australia
#9
RANDOMIZED CONTROLLED TRIAL
Jon D Emery, Victoria Gray, Fiona M Walter, Shelley Cheetham, Emma J Croager, Terry Slevin, Christobel Saunders, Timothy Threlfall, Kirsten Auret, Anna K Nowak, Elizabeth Geelhoed, Max Bulsara, C D'Arcy J Holman
BACKGROUND: Rural Australians have poorer survival for most common cancers, due partially to later diagnosis. Internationally, several initiatives to improve cancer outcomes have focused on earlier presentation to healthcare and timely diagnosis. We aimed to measure the effect of community-based symptom awareness and general practice-based educational interventions on the time to diagnosis in rural patients presenting with breast, prostate, colorectal or lung cancer in Western Australia...
November 7, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28594895/atp-sensitive-potassium-katp-channel-openers-diazoxide-and-nicorandil-lower-intraocular-pressure-by-activating-the-erk1-2-signaling-pathway
#10
Uttio Roy Chowdhury, Cindy K Bahler, Bradley H Holman, Michael P Fautsch
Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD)...
2017: PloS One
https://www.readbyqxmd.com/read/28368040/doscats-double-standards-for-protein-quantification
#11
Richard J Bennett, Deborah M Simpson, Stephen W Holman, Sheila Ryan, Philip Brownridge, Claire E Eyers, John Colyer, Robert J Beynon
The two most common techniques for absolute protein quantification are based on either mass spectrometry (MS) or on immunochemical techniques, such as western blotting (WB). Western blotting is most often used for protein identification or relative quantification, but can also be deployed for absolute quantification if appropriate calibration standards are used. MS based techniques offer superior data quality and reproducibility, but WB offers greater sensitivity and accessibility to most researchers. It would be advantageous to apply both techniques for orthogonal quantification, but workflows rarely overlap...
April 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28330466/the-nasopharyngeal-microbiota-of-beef-cattle-before-and-after-transport-to-a-feedlot
#12
Devin B Holman, Edouard Timsit, Samat Amat, D Wade Abbott, Andre G Buret, Trevor W Alexander
BACKGROUND: The nasopharyngeal (NP) microbiota plays an important role in bovine health, comprising a rich and diverse microbial community. The nasopharynx is also the niche for potentially pathogenic agents which are associated with bovine respiratory disease (BRD), a serious and costly illness in feedlot cattle. We used 14 beef heifers from a closed and disease-free herd to assess the dynamics of the NP microbiota of cattle that are transported to a feedlot. Cattle were sampled prior to transport to the feedlot (day 0) and at days 2, 7, and 14...
March 22, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/27988204/smad-transcription-factors-are-altered-in-cell-models-of-hd-and-regulate-htt-expression
#13
K R Bowles, T Stone, P Holmans, N D Allen, S B Dunnett, L Jones
Transcriptional dysregulation is observable in multiple animal and cell models of Huntington's disease, as well as in human blood and post-mortem caudate. This contributes to HD pathogenesis, although the exact mechanism by which this occurs is unknown. We therefore utilised a dynamic model in order to determine the differential effect of growth factor stimulation on gene expression, to highlight potential alterations in kinase signalling pathways that may be in part responsible for the transcriptional dysregulation observed in HD, and which may reveal new therapeutic targets...
February 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27651495/dynamic-regulation-of-auxin-oxidase-and-conjugating-enzymes-atdao1-and-gh3-modulates-auxin-homeostasis
#14
Nathan Mellor, Leah R Band, Aleš Pěnčík, Ondřej Novák, Afaf Rashed, Tara Holman, Michael H Wilson, Ute Voß, Anthony Bishopp, John R King, Karin Ljung, Malcolm J Bennett, Markus R Owen
The hormone auxin is a key regulator of plant growth and development, and great progress has been made understanding auxin transport and signaling. Here, we show that auxin metabolism and homeostasis are also regulated in a complex manner. The principal auxin degradation pathways in Arabidopsis include oxidation by Arabidopsis thaliana gene DIOXYGENASE FOR AUXIN OXIDATION 1/2 (AtDAO1/2) and conjugation by Gretchen Hagen3s (GH3s). Metabolic profiling of dao1-1 root tissues revealed a 50% decrease in the oxidation product 2-oxoindole-3-acetic acid (oxIAA) and increases in the conjugated forms indole-3-acetic acid aspartic acid (IAA-Asp) and indole-3-acetic acid glutamic acid (IAA-Glu) of 438- and 240-fold, respectively, whereas auxin remains close to the WT...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27644981/protein-turnover-measurement-using-selected-reaction-monitoring-mass-spectrometry-srm-ms
#15
Stephen W Holman, Dean E Hammond, Deborah M Simpson, John Waters, Jane L Hurst, Robert J Beynon
Protein turnover represents an important mechanism in the functioning of cells, with deregulated synthesis and degradation of proteins implicated in many diseased states. Therefore, proteomics strategies to measure turnover rates with high confidence are of vital importance to understanding many biological processes. In this study, the more widely used approach of non-targeted precursor ion signal intensity (MS1) quantification is compared with selected reaction monitoring (SRM), a data acquisition strategy that records data for specific peptides, to determine if improved quantitative data would be obtained using a targeted quantification approach...
October 28, 2016: Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences
https://www.readbyqxmd.com/read/27617304/epigenetic-remodeling-regulates-transcriptional-changes-between-ovarian-cancer-and-benign-precursors
#16
Kevin M Elias, Megan M Emori, Thomas Westerling, Henry Long, Anna Budina-Kolomets, Fugen Li, Emily MacDuffie, Michelle R Davis, Alexander Holman, Brian Lawney, Matthew L Freedman, John Quackenbush, Myles Brown, Ronny Drapkin
Regulation of lineage-restricted transcription factors has been shown to influence malignant transformation in several types of cancer. Whether similar mechanisms are involved in ovarian cancer pathogenesis is unknown. PAX8 is a nuclear transcription factor that controls the embryologic development of the Müllerian system, including the fallopian tubes. Recent studies have shown that fallopian tube secretory epithelial cells (FTSECs) give rise to the most common form of ovarian cancer, high-grade serous ovarian carcinomas (HGSOCs)...
August 18, 2016: JCI Insight
https://www.readbyqxmd.com/read/27470510/12-s-hetre-a-12-lipoxygenase-oxylipin-of-dihomo-%C3%AE-linolenic-acid-inhibits-thrombosis-via-g%C3%AE-s-signaling-in-platelets
#17
Jennifer Yeung, Benjamin E Tourdot, Reheman Adili, Abigail R Green, Cody J Freedman, Pilar Fernandez-Perez, Johnny Yu, Theodore R Holman, Michael Holinstat
OBJECTIVE: Dietary supplementation with polyunsaturated fatty acids has been widely used for primary and secondary prevention of cardiovascular disease in individuals at risk; however, the cardioprotective benefits of polyunsaturated fatty acids remain controversial because of lack of mechanistic and in vivo evidence. We present direct evidence that an omega-6 polyunsaturated fatty acid, dihomo-γ-linolenic acid (DGLA), exhibits in vivo cardioprotection through 12-lipoxygenase (12-LOX) oxidation of DGLA to its reduced oxidized lipid form, 12(S)-hydroxy-8Z,10E,14Z-eicosatrienoic acid (12(S)-HETrE), inhibiting platelet activation and thrombosis...
October 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27400856/genome-wide-common-and-rare-variant-analysis-provides-novel-insights-into-clozapine-associated-neutropenia
#18
S E Legge, M L Hamshere, S Ripke, A F Pardinas, J I Goldstein, E Rees, A L Richards, G Leonenko, L F Jorskog, K D Chambert, D A Collier, G Genovese, I Giegling, P Holmans, A Jonasdottir, G Kirov, S A McCarroll, J H MacCabe, K Mantripragada, J L Moran, B M Neale, H Stefansson, D Rujescu, M J Daly, P F Sullivan, M J Owen, M C O'Donovan, J T R Walters
The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses...
October 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/27367033/analogs-of-the-atp-sensitive-potassium-katp-channel-opener-cromakalim-with-in-vivo-ocular-hypotensive-activity
#19
Uttio Roy Chowdhury, Kimberly B Viker, Kristen L Stoltz, Bradley H Holman, Michael P Fautsch, Peter I Dosa
ATP-sensitive potassium (KATP) channel openers have emerged as potential therapeutics for the treatment of glaucoma, lowering intraocular pressure (IOP) in animal models and cultured human anterior segments. We have prepared water-soluble phosphate and dipeptide derivatives of the KATP channel opener cromakalim and evaluated their IOP lowering capabilities in vivo. In general, the phosphate derivatives proved to be more chemically robust and efficacious at lowering IOP with once daily dosing in a normotensive mouse model...
July 14, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27170315/rna-seq-of-huntington-s-disease-patient-myeloid-cells-reveals-innate-transcriptional-dysregulation-associated-with-proinflammatory-pathway-activation
#20
James R C Miller, Kitty K Lo, Ralph Andre, Davina J Hensman Moss, Ulrike Träger, Timothy C Stone, Lesley Jones, Peter Holmans, Vincent Plagnol, Sarah J Tabrizi
Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus...
July 15, 2016: Human Molecular Genetics
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