228 results on '"Riley PA"'
Search Results
2. Emergent Esophagectomy in Patients with Esophageal Malignancy Is Associated with Higher Rates of Perioperative Complications but No Independent Impact on Short-Term Mortality
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Yahya Alwatari, Devon C. Freudenberger, Jad Khoraki, Lena Bless, Riley Payne, Walker A. Julliard, Rachit D. Shah, and Carlos A. Puig
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emergent ,esophagectomy ,perioperative outcomes ,national surgical quality improvement program ,Medicine (General) ,R5-920 - Abstract
Background: Data on perioperative outcomes of emergent versus elective resection in esophageal cancer patients requiring esophagectomy are lacking. We investigated whether emergent resection was associated with increased risks of morbidity and mortality. Methods: Data on patients with esophageal malignancy who underwent esophagectomy from 2005 to 2020 were retrospectively analyzed from the American College of Surgeons National Surgical Quality Improvement Program database. Thirty-day complication and mortality rates were compared between emergent esophagectomy (EE) and non-emergent esophagectomy. Logistic regression assessed factors associated with complications and mortality. Results: Of 10,067 patients with malignancy who underwent esophagectomy, 181 (1.8%) had EE, 64% had preoperative systemic inflammatory response syndrome, sepsis, or septic shock, and 44% had bleeding requiring transfusion. The EE group had higher American Society of Anesthesiologists (ASA) class and functional dependency. More transhiatal esophagectomies and diversions were performed in the EE group. After EE, the rates of 30-day mortality (6.1% vs. 2.8%), overall complications (65.2% vs. 44.2%), bleeding, pneumonia, prolonged intubation, and positive margin (17.7% vs. 7.4%) were higher, while that of anastomotic leak was similar. On adjusted logistic regression, older age, lower albumin, higher ASA class, and fragility were associated with increased complications and mortality. McKeown esophagectomy and esophageal diversion were associated with a higher risk of postoperative complications. EE was associated with 30-day postoperative complications (odds ratio, 2.39; 95% confidence interval, 1.66–3.43; p
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- 2024
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3. Metabolomics in severe traumatic brain injury: a scoping review
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Riley Page Fedoruk, Chel Hee Lee, Mohammad Mehdi Banoei, and Brent W. Winston
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Traumatic brain injury (TBI) ,Severe traumatic brain injury (sTBI) ,Metabolomics ,Scoping review ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Diagnosis and prognostication of severe traumatic brain injury (sTBI) continue to be problematic despite years of research efforts. There are currently no clinically reliable biomarkers, though advances in protein biomarkers are being made. Utilizing Omics technology, particularly metabolomics, may provide new diagnostic biomarkers for sTBI. Several published studies have attempted to determine the specific metabolites and metabolic pathways involved; these studies will be reviewed. Aims This scoping review aims to summarize the current literature concerning metabolomics in sTBI, review the comprehensive data, and identify commonalities, if any, to define metabolites with potential clinical use. In addition, we will examine related metabolic pathways through pathway analysis. Methods Scoping review methodology was used to examine the current literature published in Embase, Scopus, PubMed, and Medline. An initial 1090 publications were identified and vetted with specific inclusion criteria. Of these, 20 publications were selected for further examination and summary. Metabolic data was classified using the Human Metabolome Database (HMDB) and arranged to determine the ‘recurrent’ metabolites and classes found in sTBI. To help understand potential mechanisms of injury, pathway analysis was performed using these metabolites and the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database. Results Several metabolites related to sTBI and their effects on biological pathways were identified in this review. Across the literature, proline, citrulline, lactate, alanine, valine, leucine, and serine all decreased in adults post sTBI, whereas both octanoic and decanoic acid increased. Hydroxy acids and organooxygen compounds generally increased following sTBI, while most carboxylic acids decreased. Pathway analysis showed significantly affected glycine and serine metabolism, glycolysis, branched-chain amino acid (BCAA) metabolism, and other amino acid metabolisms. Interestingly, no tricarboxylic acid cycle metabolites were affected. Conclusion Aside from a select few metabolites, classification of a metabolic profile proved difficult due to significant ambiguity between study design, sample size, type of sample, metabolomic detection techniques, and other confounding variables found in sTBI literature. Given the trends found in some studies, further metabolomics investigation of sTBI may be useful to identify clinically relevant metabolites.
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- 2023
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4. Does Iron Chelation by Melanin Explain the Ethnic Link with Covid-19 Fatality?
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Riley, PA, primary
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- 2020
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5. 1183 Development of CTIM-76, a highly specific Claudin 6 bispecific antibody
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Kelly Byrnes-Blake, Kate Slovik, Joseph Rucker, Ileine Sanchez, Kyle Doolan, Breanna Tyrell, Anna Lobley, Nicholas Molino, Kristin Shema, Kyle Guldner, Hayley Roth, Alyssa Cunningham, Eric Butz, Stanley Roberts, Riley Payne, Ed Calamai, and Ross Chambers
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
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6. Combining outlier analysis algorithms to identify new physics at the LHC
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Melissa van Beekveld, Sascha Caron, Luc Hendriks, Paul Jackson, Adam Leinweber, Sydney Otten, Riley Patrick, Roberto Ruiz de Austri, Marco Santoni, and Martin White
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Phenomenological Models ,Supersymmetry Phenomenology ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Abstract The lack of evidence for new physics at the Large Hadron Collider so far has prompted the development of model-independent search techniques. In this study, we compare the anomaly scores of a variety of anomaly detection techniques: an isolation forest, a Gaussian mixture model, a static autoencoder, and a β-variational autoencoder (VAE), where we define the reconstruction loss of the latter as a weighted combination of regression and classification terms. We apply these algorithms to the 4-vectors of simulated LHC data, but also investigate the performance when the non-VAE algorithms are applied to the latent space variables created by the VAE. In addition, we assess the performance when the anomaly scores of these algorithms are combined in various ways. Using super- symmetric benchmark points, we find that the logical AND combination of the anomaly scores yielded from algorithms trained in the latent space of the VAE is the most effective discriminator of all methods tested.
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- 2021
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7. Naevogenesis: A Hypothesis Concerning the Control of Proliferation of Melanocytes with Special Reference to the Growth of Intradermal Naevi
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Riley Pa
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Keratinocytes ,Cytoplasm ,Pathology ,medicine.medical_specialty ,Cell division ,Population ,Cell Communication ,Dermatology ,Melanocyte ,Biology ,Cytoplasmic Granules ,Melanin ,Phagocytosis ,medicine ,Humans ,Nevus ,education ,Cell Size ,Melanins ,education.field_of_study ,Dendrites ,medicine.disease ,Cell biology ,medicine.anatomical_structure ,Vacuoles ,Melanocytes ,Nevus, Intradermal ,Epidermis ,Melanocyte proliferation ,Keratinocyte ,Cell Division - Abstract
The pigmentary function of epidermal melanocytes depends on the donation of melanin granules to the surrounding surface structures. This involves transfer of cytoplasm (cytocrine transfer) from melanocytes to keratocytes, a process which requires competence of the donor cells and the availability of adjacent competent recipient cells. Donor cell competence involves the extension of dendrites and recipient cell competence consists of the ability of these cells to phagocytose peripheral portions of the melanocyte cytoplasm. Since there is a highly regulated mechanism for the control of cellular size which operates by inhibiting proliferation of cells that are below a critical volume, it is proposed that the continual removal of portions of the melanocyte cytoplasm by cytocrine transfer is responsible for inhibiting growth of the epidermal melanocyte population, accounting for their relatively low population density. It is proposed that inhibition of cytocrine transfer permits the proliferation of melanocytes. Cytocrine transfer may be inhibited by loss of competence of donor or recipient cells or by their relative displacement. Displacement of melanocytes into the dermis, out of range of potential recipient keratocytes, would, according to this hypothesis, result in melanocyte proliferation leading to the generation of localized aggregations of melanocytes (melanocytomas). It is proposed that this is the origin of acquired benign pigmented moles.
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- 1997
8. Free Radicals in Biology: Oxidative Stress and the Effects of Ionizing Radiation
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Riley Pa
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chemistry.chemical_classification ,Reactive oxygen species ,Cell Death ,Free Radicals ,Radiological and Ultrasound Technology ,biology ,Hydroxyl Radical ,Superoxide ,Radical ,Radiobiology ,medicine.disease_cause ,Superoxide dismutase ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Catalase ,medicine ,Biophysics ,biology.protein ,Radiology, Nuclear Medicine and imaging ,Hydroxyl radical ,Radiation Injuries ,Reactive Oxygen Species ,Oxidative stress ,Free-radical theory of aging - Abstract
The most important electron acceptor in the biosphere is molecular oxygen which, by virtue of its bi-radical nature, readily accepts unpaired electrons to give rise to a series of partially reduced species collectively known as reduced (or 'reactive') oxygen species (ROS). These include superoxide (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.) and peroxyl (ROO.) and alkoxyl (RO.) radicals which may be involved in the initiation and propagation of free radical chain reactions and which are potentially highly damaging to cells. Mechanisms have evolved to restrict and control such processes, partly by compartmentation, and partly by antioxidant defences such as chain-breaking antioxidant compounds capable forming stable free radicals (e.g. ascorbate, alpha-tocopherol) and the evolution of enzyme systems (e.g. superoxide dismutase, catalase, peroxidases) that diminish the intracellular concentration of the ROS. Although some ROS perform useful functions, the production of ROS exceeding the ability of the organism to mount an antioxidant defence results in oxidative stress and the ensuing tissue damage may be involved in certain disease processes. Evidence that ROS are involved in primary pathological mechanisms is a feature mainly of extraneous physical or chemical perturbations of which radiation is perhaps the major contributor. One of the important radiation-induced free-radical species is the hydroxyl radical which indiscriminately attacks neighbouring molecules often at near diffusion-controlled rates. Hydroxyl radicals are generated by ionizing radiation either directly by oxidation of water, or indirectly by the formation of secondary partially ROS. These may be subsequently converted to hydroxyl radicals by further reduction ('activation') by metabolic processes in the cell. Secondary radiation injury is therefore influenced by the cellular antioxidant status and the amount and availability of activating mechanisms. The biological response to radiation may be modulated by alterations in factors affecting these secondary mechanisms of cellular injury.
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- 1994
9. Is the Initial Event in Carcinogenesis An Enhancement of the Mutation Rate?
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Riley Pa
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Adult ,Mutation rate ,Free Radicals ,Population ,Clone (cell biology) ,Biology ,medicine.disease_cause ,Models, Biological ,Biochemistry ,Lesion ,Neoplasms ,medicine ,Humans ,education ,Aged ,Probability ,Aged, 80 and over ,Genetics ,education.field_of_study ,Incidence (epidemiology) ,Age Factors ,Cancer ,Middle Aged ,medicine.disease ,Cell Transformation, Neoplastic ,Mutagenesis ,Mutation (genetic algorithm) ,medicine.symptom ,Carcinogenesis ,Precancerous Conditions ,DNA Damage - Abstract
The age-specific incidence rates of adult cancer indicate that the carcinogenic process is a power function of elapsed time. If the malignant clone arises by a series of mutations, and each mutation is regarded as an independent event with a small instantaneous probability of occurrence, then the slope of the age-specific incidence gives an indication of the number of genes involved. In most cases, the epidemiological data exhibit an age-specific incidence the slope of which is between a fourth and a seventh power of age. Assuming that the mutations involved are deletions and must occur in otherwise viable and proliferative cells, the mutation rate required to generate enough mutant cells to fit the cancer incidence data must be remarkably high in the pre-malignant cell population. The initiation process may thus be an event that results in a raised mutation rate in the affected cell and its progeny. It is proposed that the process of induction involves one or more mutations that induce a metabolic lesion that has the effect of increasing the subsequent mutation rate in the affected clone. A possible mechanism involving free radical generation is suggested and some of the biological implications of the proposal examined.
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- 1990
10. Signal versus background interference in H + → t b ¯ $$ {H}^{+}\to t\overline{b} $$ signals for MSSM benchmark scenarios
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Abdesslam Arhrib, Duarte Azevedo, Rachid Benbrik, Hicham Harouiz, Stefano Moretti, Riley Patrick, and Rui Santos
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Supersymmetry Phenomenology ,Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
Abstract In this paper, we investigate sizeable interference effects between a heavy charged Higgs boson signal produced dominantly via gg → t b ¯ H − $$ gg\to t\overline{b}{H}^{-} $$ (+ c.c.) followed by the decay H − → b t ¯ $$ {H}^{-}\to b\overline{t} $$ (+ c.c.) and the irreducible background given by pp → t t ¯ b b ¯ $$ pp\to t\overline{t}b\overline{b} $$ topologies at the Large Hadron Collider (LHC). We show that it may be possible that such effects could spoil current H ± searches where signal and background are normally treated separately. The reason for this is that a heavy charged Higgs boson can have a large total width, in turn enabling such interferences, altogether leading to potentially very significant alterations, both at the inclusive and exclusive level, of the yield induced by the signal alone. This therefore implies that currently established LHC searches for such wide charged Higgs bosons might require modifications. We show such effects quantitatively using two different benchmark configurations of the minimal realisation of Supersymmetry, wherein such H ± states naturally exist. However, on the basis of the limited computing resources available, we are unable to always bring the statistical error down to a level where all such interference effects are unequivocal, so that we advocate dedicated experimental analyses to confirm this with higher statistics data samples.
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- 2020
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11. ER-luminal [Ca2+] regulation of InsP3 receptor gating mediated by an ER-luminal peripheral Ca2+-binding protein
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Horia Vais, Min Wang, Karthik Mallilankaraman, Riley Payne, Chris McKennan, Jeffrey T Lock, Lynn A Spruce, Carly Fiest, Matthew Yan-lok Chan, Ian Parker, Steven H Seeholzer, J Kevin Foskett, and Don-On Daniel Mak
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inositol 1,4,5-trisphosphate receptor ,single-channel gating regulation ,intracellular calcium-release channel ,annexin ,endoplasmic reticulum lumen ,calcium signaling ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Modulating cytoplasmic Ca2+ concentration ([Ca2+]i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca2+]ER. The widely-expressed Ca2+-binding protein annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a luminal region of the channel, can modify high-[Ca2+]ER inhibition of InsP3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP3R channel activity and InsP3R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.
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- 2020
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12. Variable Assembly of EMRE and MCU Creates Functional Channels with Distinct Gatekeeping Profiles
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Riley Payne, Carmen Li, and J. Kevin Foskett
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Science - Abstract
Summary: MCU is a Ca2+-selective channel that mediates mitochondrial Ca2+ influx. The human channel contains tetrameric pore-forming MCU, regulatory subunits MICU1/2, and EMRE that is required both for channel function and MICU1/2-mediated Ca2+ regulation. A structure of MCU with EMRE revealed a 4:4 stoichiometry, but the stoichiometry in vivo is unknown. Expression of tagged EMRE and MCU at a 1:10 ratio in cells lacking EMRE and MCU restored channel activity but not full channel gatekeeping. Increasing EMRE expression enhanced gatekeeping, raising the cytoplasmic Ca2+ concentration ([Ca2+]c) threshold for channel activation. MCU-EMRE concatemers creating channels with 1EMRE:4MCU restored Ca2+ uptake in cells, whereas cells expressing concatemers that enforced a 4EMRE:4MCU stoichiometry demonstrated enhanced channel gatekeeping. Concatemers enforcing 2EMRE/4MCU recapitulated the activity, gatekeeping, and size of endogenous channels. Thus, MCU does not require four EMRE, with most endogenous channels containing two, but complexes with 1–4 EMRE have activity with full or partial gatekeeping. : Molecular Biology; Molecular Structure Subject Areas: Molecular Biology, Molecular Structure
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- 2020
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13. Triple top signal as a probe of charged Higgs in a 2HDM
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Riley Patrick, Pankaj Sharma, and Anthony G. Williams
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Physics ,QC1-999 - Abstract
Within the framework of the type-II Two Higgs Doublet Model (2HDM-II) we study the production of three top quarks at the Large Hadron Collider (LHC). In the Standard Model the production cross section of three tops is low (≈3 fb), while it is expected to be significant in the 2HDM-II for reasonable choices of the parameters. We study the production of a charged Higgs in association with a top quark, followed by the decays H±→W±A and A→tt¯. We undertake a full detector simulation of the signal, and use simple conservative cuts, focussing on the final states that contain three or more leptons, and exactly one same sign di-lepton pair. Finally, we present the exclusion bounds dependent on charged Higgs and pseudoscalar Higgs masses expected in the near future at the 14 TeV LHC. Keywords: 2HDM, Multi-top production, Charged Higgs
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- 2018
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14. MICU2 Restricts Spatial Crosstalk between InsP3R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU
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Riley Payne, Henry Hoff, Anne Roskowski, and J. Kevin Foskett
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mitochondria ,calcium ,uniporter ,inositol trisphosphate receptor ,nanodomain ,Biology (General) ,QH301-705.5 - Abstract
Ca2+ entry into mitochondria is mediated by the Ca2+ uniporter-channel complex containing MCU, the Ca2+-selective pore, and associated regulatory proteins. The roles of MICU proteins are controversial. MICU1 was proposed to be necessary for MCU activity, whereas subsequent studies suggested it inhibits the channel in the low-cytoplasmic Ca2+ ([Ca2+]c) regime, a mechanism referred to as “gatekeeping,” that imposes a [Ca2+]c threshold for channel activation at ∼1–3 μM. Here, we measured MCU activity over a wide range of quantitatively controlled and recorded [Ca2+]c. MICU1 alone can mediate gatekeeping as well as highly cooperative activation of MCU activity, whereas the fundamental role of MICU2 is to regulate the threshold and gain of MICU1-mediated inhibition and activation of MCU. Our results provide a unifying model for the roles of the MICU1/2 heterodimer in MCU-channel regulation and suggest an evolutionary role for MICU2 in spatially restricting Ca2+ crosstalk between single inositol 1,4,5-trisphosphate receptor (InsP3R) and MCU channels.
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- 2017
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15. Comparison of δ-aminolaevulinic acid and its methyl ester as an inducer of porphyrin synthesis in cultured cells
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Washbrook, R, primary and Riley, PA, additional
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- 1997
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16. The synthesis and biological evaluation of phosphate triester alkyl lysophospholipids (ALPs) as potential antineoplastic and anti-HIV agents
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Wang, Y., primary, McGuigan, C., additional, Hay, AJ., additional, Mahmood, N., additional, Balzarini, J., additional, De Clercq, E., additional, and Riley, PA., additional
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- 1995
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17. The synthesis of novel phospholipids with potential antineoplastic and antiviral activity
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Wilson, MS., primary, McGuigan, C., additional, Hay, A.J., additional, Mahmood, N., additional, Balzarini, J., additional, De Clercq, E., additional, Postle, A., additional, and Riley, PA., additional
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- 1995
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18. Increased activity of 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase in purified cell suspensions and single cells from the uterine cervix in cervical intraepithelial neoplasia
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Jonas, SK, primary, Benedetto, C, additional, Flatman, A, additional, Hammond, RH, additional, Micheletti, L, additional, Riley, C, additional, Riley, PA, additional, Spargo, DJ, additional, Zonca, M, additional, and Slater, TF, additional
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- 1992
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19. Exploring a heavy charged Higgs using jet substructure in a fully hadronic channel
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Riley Patrick, Pankaj Sharma, and Anthony G. Williams
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Nuclear and particle physics. Atomic energy. Radioactivity ,QC770-798 - Abstract
In the framework of the type-II Two Higgs Doublet Model (2HDM-II) a charged Higgs search strategy is presented for the dominant production mode gb→tH± at the 14 TeV LHC. We consider the decay process which includes t→bW± and H±→AW±, and a fully hadronic final state consisting of bbb¯+jets+X. Dictated by the b→sγ constraints which render MH±>480 GeV we study two scenarios in which the charged Higgs mass is 750 GeV and the pseudoscalar Higgs mass is 200 GeV and 500 GeV. In this mass scheme highly boosted final state objects are expected and handled with jet substructure techniques which also acts to suppress the standard model background. A detailed detector analysis is performed, followed by a multivariate analysis involving many kinematic variables to optimize signal to background significance. Finally the LHC search sensitivities for the two scenarios are presented for various integrated luminosities.
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- 2017
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20. EMRE Is a Matrix Ca2+ Sensor that Governs Gatekeeping of the Mitochondrial Ca2+ Uniporter
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Horia Vais, Karthik Mallilankaraman, Don-On Daniel Mak, Henry Hoff, Riley Payne, Jessica E. Tanis, and J. Kevin Foskett
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Biology (General) ,QH301-705.5 - Abstract
The mitochondrial uniporter (MCU) is an ion channel that mediates Ca2+ uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca2+ signaling. Matrix Ca2+ concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca2+ overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca2+ concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake, and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca2+. Thus, mitochondria are protected from Ca2+ depletion and Ca2+ overload by a unique molecular complex that involves Ca2+ sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.
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- 2016
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21. The African Health Profession Regulatory Collaborative for Nurses and Midwives
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McCarthy Carey F and Riley Patricia L
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Health workforce ,Regulation ,Health profession ,Human resources for health ,Collaborative ,Global health ,Regional approach ,Strengthening ,Nursing ,Midwifery ,Medicine (General) ,R5-920 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background More than thirty-five sub-Saharan African countries have severe health workforce shortages. Many also struggle with a mismatch between the knowledge and competencies of health professionals and the needs of the populations they serve. Addressing these workforce challenges requires collaboration among health and education stakeholders and reform of health worker regulations. Health professional regulatory bodies, such as nursing and midwifery councils, have the mandate to reform regulations yet often do not have the resources or expertise to do so. In 2011, the United States of America Centers for Disease Control and Prevention began a four-year initiative to increase the collaboration among national stakeholders and help strengthen the capacity of health professional regulatory bodies to reform national regulatory frameworks. The initiative is called the African Health Regulatory Collaborative for Nurses and Midwives. This article describes the African Health Regulatory Collaborative for Nurses and Midwives and discusses its importance in implementing and sustaining national, regional, and global workforce initiatives. Discussion The African Health Profession Regulatory Collaborative for Nurses and Midwives convenes leaders responsible for regulation from 14 countries in East, Central and Southern Africa. It provides a high profile, south-to-south collaboration to assist countries in implementing joint approaches to problems affecting the health workforce. Implemented in partnership with Emory University, the Commonwealth Secretariat, and the East, Central and Southern African College of Nursing, this initiative also supports four to five countries per year in implementing locally-designed regulation improvement projects. Over time, the African Health Regulatory Collaborative for Nurses and Midwives will help to increase the regulatory capacity of health professional organizations and ultimately improve regulation and professional standards in this region of Africa. The African Health Regulatory Collaborative for Nurses and Midwives will measure the progress of country projects and conduct an annual evaluation of the initiative’s regional impact, thereby contributing to the global evidence base of health workforce interventions. Conclusion The African Health Regulatory Collaborative for Nurses and Midwives is designed to address priority needs in health workforce development and improve regulation of the health workforce. This model may assist others countries and regions facing similar workforce challenges.
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- 2012
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22. Information systems on human resources for health: a global review
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Riley Patricia L, Zuber Alexandra, Vindigni Stephen M, Gupta Neeru, Verani Andre R, Sunderland Nadine L, Friedman Michael, Zurn Pascal, Okoro Chijioke, Patrick Heather, and Campbell James
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Human resources information system ,HRIS ,Human resources for health ,Literature review ,Workforce surveillance ,Workforce science ,Global health ,Medicine (General) ,R5-920 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Background Although attainment of the health-related Millennium Development Goals relies on countries having adequate numbers of human resources for health (HRH) and their appropriate distribution, global understanding of the systems used to generate information for monitoring HRH stock and flows, known as human resources information systems (HRIS), is minimal. While HRIS are increasingly recognized as integral to health system performance assessment, baseline information regarding their scope and capability around the world has been limited. We conducted a review of the available literature on HRIS implementation processes in order to draw this baseline. Methods Our systematic search initially retrieved 11 923 articles in four languages published in peer-reviewed and grey literature. Following the selection of those articles which detailed HRIS implementation processes, reviews of their contents were conducted using two-person teams, each assigned to a national system. A data abstraction tool was developed and used to facilitate objective assessment. Results Ninety-five articles with relevant HRIS information were reviewed, mostly from the grey literature, which comprised 84 % of all documents. The articles represented 63 national HRIS and two regionally integrated systems. Whereas a high percentage of countries reported the capability to generate workforce supply and deployment data, few systems were documented as being used for HRH planning and decision-making. Of the systems examined, only 23 % explicitly stated they collect data on workforce attrition. The majority of countries experiencing crisis levels of HRH shortages (56 %) did not report data on health worker qualifications or professional credentialing as part of their HRIS. Conclusion Although HRIS are critical for evidence-based human resource policy and practice, there is a dearth of information about these systems, including their current capabilities. The absence of standardized HRIS profiles (including documented processes for data collection, management, and use) limits understanding of the availability and quality of information that can be used to support effective and efficient HRH strategies and investments at the national, regional, and global levels.
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- 2012
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23. Evaluating compliance to a low glycaemic index (GI) diet in women with polycystic ovary syndrome (PCOS)
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Atiomo William, Riley Paddy, Read Anna, and Egan Nicola
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Medicine ,Biology (General) ,QH301-705.5 ,Science (General) ,Q1-390 - Abstract
Abstract Background A low Glycaemic Index (GI) diet may decrease some long-term health risks in Polycystic Ovary Syndrome (PCOS) such as endometrial cancer. This study was performed to assess compliance to a low GI diet in women with PCOS. Food diaries prospectively collected over 6 months from women on a low GI diet or healthy eating diet were analysed retrospectively. The women were recruited for a pilot randomised control trial investigating whether a low GI diet decreased the risk of Endometrial Cancer. Nine women with PCOS completed 33 food diaries (17 from women on a low GI diet and 16 from women on a healthy eating diet) recording 3023 food items (low GI group:n = 1457; healthy eating group:n = 1566). Data was analysed using Foster-Powell international values inserted into an SPSS database as no scientifically valid established nutrition software was found. The main outcome measures were mean item GI and Glyacemic Load (GL), mean meal GL, percentage high GI foods and mean weight loss. Findings Women allocated the low GI diet had a statistically significant lower GI of food items (33.67 vs 36.91, p < 0.05), lower percentage of high GI foods (4.3% vs 12.1%, p < 0.05) and lower GL of food items and meals. Conclusion Women with PCOS on a low GI diet consumed food items with a significantly lower mean GI and GL compared to the healthy eating diet group. Longer term compliance needs evaluation in subsequent studies to ascertain that this translates to reduced long term health risks. Trial Registration ISRCTN: ISRCTN86420258
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- 2011
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24. Impact of removing the healthcare mask mandate on hospital-acquired COVID-19 rates.
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Mehra R, Patterson BJ, Riley PA, Planche TD, and Breathnach AS
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- Humans, SARS-CoV-2, Pandemics prevention & control, Masks, Hospitals, COVID-19 epidemiology, COVID-19 prevention & control
- Abstract
Background: Mandatory mask-wearing policies were one of several measures employed to reduce hospital-acquired SARS-CoV-2 infection throughout the pandemic. Many nations have removed healthcare mask mandates, but there remains a risk of new SARS-CoV-2 variants or epidemics of other respiratory viruses., Aim: To demonstrate the impact of removing the healthcare mask mandate., Methods: SARS-CoV-2 infections were analysed in a large teaching hospital for 40 weeks in 2022 using a controlled interrupted time-series design. The intervention was the removal of a staff/visitor surgical mask-wearing policy for the most wards at week 26 (intervention group) with a subset of specific wards retaining the mask policy (control group). The hospital-acquired SARS-CoV-2 infection rate was adjusted by the underlying community infection rate., Findings: In the context of a surge in SARS-CoV-2 infection, removal of the mask mandate for staff/visitors was not associated with a statistically significant change in the rate of nosocomial SARS-CoV-2 infection in the intervention group (incidence rate ratio: 1.105; 95% confidence interval: 0.523-2.334; P = 0.79) and there was no post-intervention trend (1.013; 0.932-1.100; P = 0.76) to suggest a delayed effect. The control group also showed no immediate or delayed change in infection rate., Conclusion: No evidence was found that removal of a staff/visitor mask-wearing policy had a significant effect on the rate of hospital-acquired SARS-CoV-2 infection. This does not demonstrate that masks were ineffective through the pandemic, but provides some objective evidence to justify the removal of healthcare mask mandates once there was widespread immunity and reduced disease severity., (Copyright © 2023 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)
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- 2024
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25. Does iron chelation by eumelanin contribute to the ethnic link with maternal mortality?
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Edge R, Riley PA, and Truscott TG
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- Humans, Iron Chelating Agents, Melanins, Female, Maternal Mortality, Chelation Therapy
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2022
- Full Text
- View/download PDF
26. A Retrospective Real-World Study of the Effectiveness and Tolerability of Tildrakizumab in UK Adults with Moderate-to-Severe Chronic Plaque Psoriasis.
- Author
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Becher G, Conner S, Ingram JA, Stephen KE, McInnes AC, Heald AH, Riley PA, Davies M, Domenech A, and Kasujee I
- Abstract
Introduction: As with most medicines historically, clinicians prescribing tildrakizumab have relied on information derived from registration studies undertaken in a prospective controlled clinical trial setting. More recently, clinicians, policymakers, and commissioners increasingly rely on real-world data to inform both policy and practice., Methods: A retrospective real-world data study was undertaken at four specialist dermatology departments in the United Kingdom. All adult patients treated with tildrakizumab for moderate-to-severe plaque psoriasis were included, with data being collected for 122 patients., Results: Psoriatic patients on tildrakizumab tended to be overweight (median body mass index of 32 (range 19-59) (n = 61); 26/68 (38%) < 90 kg, 32/68 (47%) between 90 and 120 kg, and 10/68 (15%) > 120 kg). The study population had high levels of comorbidities (83/116, 72%), multiple special sites (39/117, 33%), and histories of biological treatments (81/100, 81%). Most patients (61/80, 76%) initiated on tildrakizumab were switched from another biological treatment. Tildrakizumab was effective, with 91/122 (75%) patients remaining on treatment for the duration of the study-a median of 12 months per patient (range 1-29 months)-and achieving a change in median Psoriasis Area and Severity Index (PASI) from 12 to 0.35 and in Dermatology Life Quality Index (DLQI) from 20 to 0. The response rate was 57/66 (86%) when tildrakizumab was used as the first- or second-line biologic compared to 19/31 (61%) when used as the third- to seventh-line. Thirty-three (78.6%) patients over 90 kg of weight received the 200-mg dose of tildrakizumab. All but one (n = 8) patient with body weight over 120 kg maintained response over time. There was one treatment discontinuation; a patient who had a local sensitivity reaction., Conclusions: In UK clinical practice, tildrakizumab was well tolerated and effective at doses of 100 mg or 200 mg in a range of patient phenotypes., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
27. Prior COVID-19 protects against reinfection, even in the absence of detectable antibodies.
- Author
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Breathnach AS, Duncan CJA, Bouzidi KE, Hanrath AT, Payne BAI, Randell PA, Habibi MS, Riley PA, Planche TD, Busby JS, Sudhanva M, Pallett SJC, and Kelleher WP
- Subjects
- Antibodies, Viral, Humans, Reinfection, SARS-CoV-2, COVID-19
- Published
- 2021
- Full Text
- View/download PDF
28. Prior COVID-19 significantly reduces the risk of subsequent infection, but reinfections are seen after eight months.
- Author
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Breathnach AS, Riley PA, Cotter MP, Houston AC, Habibi MS, and Planche TD
- Subjects
- Humans, Recurrence, Reinfection, COVID-19, SARS-CoV-2
- Abstract
Competing Interests: Declarations of Competing Interest The authors declare they have no conflicts of interest.
- Published
- 2021
- Full Text
- View/download PDF
29. Thirty years of therapeutic innovation in melanoma research.
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Lejeune FJ, Storkus WJ, and Riley PA
- Subjects
- Biomedical Research, Humans, Time Factors, Melanoma drug therapy, Skin Neoplasms drug therapy
- Published
- 2021
- Full Text
- View/download PDF
30. Epimutation and Cancer: Carcinogenesis Viewed as Error-Prone Inheritance of Epigenetic Information.
- Author
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Riley PA
- Abstract
The epimutation concept, that is, malignancy is a result of deranged patterns of gene expression due to defective epigenetic control, proposes that in the majority of adult cancers the primary (initiating) lesion adversely affects the mechanism of vertical transmission of the epigenetic pattern existing in the stem cells of differentiated tissue. Such an error-prone mechanism will result in deviant gene expression capable of accumulation at each mitosis of the affected stem cell clone. It is argued that a proportion of these proliferation products will express combinations of genes which endow them with malignant properties, such as the ability to transgress tissue boundaries and migrate to distant locations. Since the likelihood of this occurrence is dependent on the proliferation of cells manifesting the defective epigenetic transmission, the theory predicts that cancer incidence will be strongly influenced by factors regulating the turnover rate of the stem cells of the tissue in question. Evidence relating to this stipulation is examined. In addition, it would be anticipated on the basis of the selection of genes involved that the susceptibility to malignant transformation will vary according to the tissue of origin and this is also discussed.
- Published
- 2018
- Full Text
- View/download PDF
31. Investigation of the anomalous action of 5-hydroxyresorcinol on tyrosinase.
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Land EJ, Ramsden CA, Riley PA, and Stratford MR
- Subjects
- Agaricus enzymology, Anisoles metabolism, Benzoquinones metabolism, Catechols metabolism, Enzyme Activation, Molecular Structure, Oxidation-Reduction, Oxygen metabolism, Phenols metabolism, Plant Proteins metabolism, Pulse Radiolysis, Substrate Specificity, Monophenol Monooxygenase metabolism, Resorcinols metabolism
- Published
- 2016
- Full Text
- View/download PDF
32. Oxidative calcium release from catechol.
- Author
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Riley PA and Stratford MR
- Subjects
- Agaricus enzymology, Calcium chemistry, Catechols chemistry, Monophenol Monooxygenase metabolism, Oxidation-Reduction, Quinones chemistry, Quinones metabolism, Calcium metabolism, Catechols metabolism
- Abstract
Oxidation of 4-methylcatechol previously exposed to aqueous calcium chloride was shown by ion chromatography to be associated with release of calcium ions. The catechol was oxidised to the corresponding orthoquinone by the use of tyrosinase from Agaricus bisporus. The oxidative release of calcium from the catechol is ascribed to the diminution of the available hydroxyl functions able to act as chelating groups. Our results suggest that the redox status of melanin may regulate calcium binding and influence calcium levels in pigmented cells., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
33. Failure of fidelity of vertical transmission of epigenetic patterning as the basis of cancer.
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Riley PA
- Subjects
- Cell Differentiation, Cell Movement, DNA Methylation, Gene Silencing, Humans, Melanoma immunology, Melanoma pathology, Mutation, Neoplasms immunology, Neoplasms pathology, Phenotype, Skin Neoplasms immunology, Skin Neoplasms pathology, Epigenesis, Genetic, Melanoma genetics, Neoplasms genetics, Skin Neoplasms genetics
- Published
- 2014
- Full Text
- View/download PDF
34. Mechanistic aspects of the tyrosinase oxidation of hydroquinone.
- Author
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Ramsden CA and Riley PA
- Subjects
- Catechols chemistry, Catechols metabolism, Hydroquinones chemistry, Molecular Structure, Monophenol Monooxygenase chemistry, Oxidation-Reduction, Phenols chemistry, Phenols metabolism, Thermodynamics, Hydroquinones metabolism, Monophenol Monooxygenase metabolism
- Abstract
Contradictory reports on the behaviour of hydroquinone as a tyrosinase substrate are reconciled in terms of the ability of the initially formed ortho-quinone to tautomerise to the thermodynamically more stable para-quinone isomer. Oxidation of phenols by native tyrosinase requires activation by in situ formation of a catechol formed via an enzyme generated ortho-quinone. In the special case of hydroquinone, catechol formation is precluded by rapid tautomerisation of the ortho-quinone precursor to catechol formation., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
35. Tyrosinase: the four oxidation states of the active site and their relevance to enzymatic activation, oxidation and inactivation.
- Author
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Ramsden CA and Riley PA
- Subjects
- Catalytic Domain, Catechols chemistry, Catechols metabolism, Kinetics, Monophenol Monooxygenase chemistry, Oxidation-Reduction, Quinones chemistry, Quinones metabolism, Resorcinols chemistry, Resorcinols metabolism, Monophenol Monooxygenase metabolism
- Abstract
Tyrosinase is an enzyme widely distributed in the biosphere. It is one of a group of proteins with a strongly conserved bicopper active centre able to bind molecular oxygen. Tyrosinase manifests two catalytic properties; monooxygenase and oxidase activity. These actions reflect the oxidation states of the active centre. Tyrosinase has four possible oxidation states and the details of their interaction are shown to give rise to the unusual kinetic behaviour of the enzyme. The resting state of the enzyme is met-tyrosinase [Cu(II)2] and activation, associated with a 'lag period', involves reduction to deoxy-tyrosinase [Cu(I)2] which is capable of binding dioxygen to form oxy-tyrosinase [Cu(II)2·O2]. Initially the conversion of met- to deoxy-tyrosinase is brought about by a catechol that is indirectly formed from an ortho-quinone product of tyrosinase action. The primary function of the enzyme is monooxygenation of phenols to ortho-quinones by oxy-tyrosinase. Inactivation of the enzyme results from monooxygenase processing of catechols which can lead to reductive elimination of one of the active-site copper ions and conversion of oxy-tyrosinase to the inactive deact-tyrosinase [Cu(II)Cu(0)]. This review describes the tyrosinase pathways and the role of each oxidation state in the enzyme's oxidative transformations of phenols and catechols., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
36. Mechanistic studies of the inactivation of tyrosinase by resorcinol.
- Author
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Stratford MR, Ramsden CA, and Riley PA
- Subjects
- Catalytic Domain, Catechols chemistry, Catechols metabolism, Copper chemistry, Copper metabolism, Kinetics, Monophenol Monooxygenase antagonists & inhibitors, Oxidation-Reduction, Oximetry, Protein Binding, Resorcinols chemistry, Spectrophotometry, Monophenol Monooxygenase metabolism, Resorcinols metabolism
- Abstract
The inactivation of tyrosinase by resorcinol (1,3-dihydroxybenzene) and seventeen simple derivatives has been investigated using combined spectrophotometry and oximetry together with hplc/ms examination of the oxidation products. The results are consistent with a Quintox mechanism, analogous to that proposed for catechol inactivation of tyrosinase, in which the resorcinol substrate is oxidised via the monooxygenase route leading to a hydroxy intermediate that undergoes deprotonation and results in irreversible elimination of Cu(0) from the active site. Hplc/ms evidence for formation of the resorcinol monooxygenase product (3-hydroxy-ortho-quinone) is presented and the relationship between the ring position of simple resorcinol substituents (H, Me, F, Cl) and tyrosinase inactivation is rationalised., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
37. The influence of hydroquinone on tyrosinase kinetics.
- Author
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Stratford MR, Ramsden CA, and Riley PA
- Subjects
- Catechols chemistry, Catechols metabolism, Chromatography, High Pressure Liquid, Dihydroxyphenylalanine chemistry, Dihydroxyphenylalanine metabolism, Hydroquinones chemistry, Kinetics, Mass Spectrometry, Oxidation-Reduction, Oximetry, Phenols chemistry, Phenols metabolism, Spectrophotometry, Hydroquinones metabolism, Monophenol Monooxygenase metabolism
- Abstract
In vitro studies, using combined spectrophotometry and oximetry together with hplc/ms examination of the products of tyrosinase action demonstrate that hydroquinone is not a primary substrate for the enzyme but is vicariously oxidised by a redox exchange mechanism in the presence of either catechol, L-3,4-dihydroxyphenylalanine or 4-ethylphenol. Secondary addition products formed in the presence of hydroquinone are shown to stimulate, rather than inhibit, the kinetics of substrate oxidation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
38. Use of Freedom of Information Act to produce research on the cheap?
- Author
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Breathnach AS, Riley PA, and Planche TD
- Subjects
- Humans, Research, Smoking, Tobacco Industry, Universities
- Published
- 2011
- Full Text
- View/download PDF
39. Rapid halogen substitution and dibenzodioxin formation during tyrosinase-catalyzed oxidation of 4-halocatechols.
- Author
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Stratford MR, Riley PA, and Ramsden CA
- Subjects
- Benzoquinones chemistry, Biocatalysis, Catechols chemistry, Chromatography, High Pressure Liquid, Mass Spectrometry, Oxidation-Reduction, Catechols metabolism, Dioxins chemistry, Halogens chemistry, Monophenol Monooxygenase metabolism
- Abstract
4-Fluoro-1,2-benzoquinone, generated by tyrosinase oxidation of 4-fluorocatechol in aqueous buffer, rapidly undergoes substitution by O-nucleophiles (water or catechols) with release of fluoride. 4-Chloro- and 4-bromocatechol behave similarly. The reactions, which have toxicological implications, have been monitored by spectrophotometry and HPLC/MS, and intermediate and final products, including dibenzodioxins, identified.
- Published
- 2011
- Full Text
- View/download PDF
40. Antibiotic prophylaxis. MRSA and Clostridium difficile are falling.
- Author
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Riley PA
- Subjects
- England epidemiology, Humans, Incidence, Clostridioides difficile, Clostridium Infections epidemiology, Methicillin-Resistant Staphylococcus aureus, Staphylococcal Infections epidemiology
- Published
- 2010
- Full Text
- View/download PDF
41. STEP: simplified treatment of the enlarged prostate.
- Author
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Rosenberg MT, Miner MM, Riley PA, and Staskin DR
- Subjects
- 5-alpha Reductase Inhibitors therapeutic use, Adrenergic beta-Agonists therapeutic use, Aged, Aged, 80 and over, Humans, Male, Middle Aged, Prostatism etiology, Prostatism therapy, Quality of Life, Referral and Consultation, Watchful Waiting, Prostatic Hyperplasia therapy
- Abstract
We propose a simple and practical approach to the identification, evaluation and treatment of lower urinary tract symptoms (LUTS) resulting from an enlarging and obstructive prostate. The proposed Simplified Treatment for Enlarged Prostate (STEP) plan is a logical guide to patient management by the primary care provider (PCP). Symptoms of enlarged prostate (EP) are common and may frequently progress into a condition with profound adverse effects on quality of life. Despite the high prevalence, EP is underdiagnosed and undertreated. This situation may result from patient- and provider-related issues. Assessment of symptoms of EP should be initiated with a discussion of LUTS. Evaluation includes a focused history, physical examination and selected laboratory tests. Certain factors put the symptomatic patient at risk for disease progression; however, not all factors can be readily evaluated in the PCP setting. The serum prostate-specific antigen (PSA) level acts both as an indicator of prostatic size and a screening tool for prostatic cancer, and thereby provides an important tool for PCPs. The STEP plan is a logical guide to patient management. Step 1, watchful waiting, is appropriate in patients with symptoms that are not bothersome. If symptoms cause bother, the initiation of an alpha-blocker (AB) in step 2, provides relatively rapid symptom improvement. Patients with bothersome symptoms and a PSA > or = 1.5 ng/ml are at risk for progression and consideration should be given to combination treatment with an AB and a 5alpha-reductase inhibitor (step 3). Patients with refractory symptoms should be referred to a urologist (step 4). Identification, evaluation and management of EP are within the domain of the primary care setting. The STEP approach provides a simple and practical framework for PCPs to manage most men with symptoms of EP.
- Published
- 2010
- Full Text
- View/download PDF
42. Guidelines for prioritisation of single-room use: a pragmatic approach.
- Author
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Breathnach AS, Zinna SS, Riley PA, and Planche TD
- Subjects
- Humans, Hospitals, United Kingdom, Practice Guidelines as Topic, Cross Infection prevention & control, Infection Control methods, Patients' Rooms statistics & numerical data
- Published
- 2010
- Full Text
- View/download PDF
43. The influence of catechol structure on the suicide-inactivation of tyrosinase.
- Author
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Ramsden CA, Stratford MR, and Riley PA
- Subjects
- Catalysis, Catalytic Domain, Catechol Oxidase metabolism, Catechols metabolism, Copper metabolism, Genes, Transgenic, Suicide, Kinetics, Molecular Structure, Oxidation-Reduction, Structure-Activity Relationship, Substrate Specificity, Catechols chemistry, Monophenol Monooxygenase metabolism
- Abstract
3,6-Difluorocatechol, which cannot act as a monooxygenase tyrosinase substrate, is an oxidase substrate, and, in contrast to other catechols, oxidation does not lead to suicide-inactivation, providing experimental evidence for an inactivation mechanism involving reductive elimination of Cu(0) from the active site.
- Published
- 2009
- Full Text
- View/download PDF
44. A reactive ortho-quinone generated by tyrosinase-catalyzed oxidation of the skin depigmenting agent monobenzone: self-coupling and thiol-conjugation reactions and possible implications for melanocyte toxicity.
- Author
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Manini P, Napolitano A, Westerhof W, Riley PA, and d'Ischia M
- Subjects
- Animals, Cattle, Glutathione, Melanocytes drug effects, Quinones analysis, Catechol Oxidase economics, Monophenol Monooxygenase metabolism
- Abstract
Monobenzone (hydroquinone monobenzylether, 1) is a potent skin depigmenting agent that causes irreversible loss of epidermal melanocytes by way of a tyrosinase-dependent mechanism so far little understood. Herein, we show that 1 can be oxidized by mushroom tyrosinase to an unstable o-quinone (1-quinone) that has been characterized by comparison of its properties with those of a synthetic sample obtained by o-iodoxybenzoic acid-mediated oxidation of 1. Preparative scale oxidation of 1 with tyrosinase and catalytic l-DOPA, followed by reductive workup and acetylation, led to the isolation of two main products that were identified as the acetylated catechol derivative 4 and an unusual biphenyl-type dimer of 4, acetylated 5, arising evidently by coupling of 4 with 1-quinone. In the presence of l-cysteine or N-acetyl-l-cysteine, formation of 4 and 5 was inhibited, and the reaction led instead to monoadducts (6 or 9) and diadducts (7 and 8). A similar behavior was observed when the tyrosinase-promoted oxidation of 1 was carried out in the presence of sulfhydryl-containing peptides, such as reduced glutathione, or proteins, such as bovine serum albumin (BSA), as inferred by detection of adduct 9 by high pressure liquid chromatography-electrochemical detection (HPLC-ED) after acid hydrolysis. The generation and reaction chemistry of 1-quinone described in this article may bear relevance to the etiopathogenetic mechanisms of monobenzone-induced leukoderma as well as to the recently proposed haptenation hypothesis of vitiligo, a disabling pigmentary disorder characterized by irreversible melanocyte loss.
- Published
- 2009
- Full Text
- View/download PDF
45. Dopamine quinone chemistry: a study of the influence of amide, amidine and guanidine substituents [-NH-CX-Y] on the mode of reaction.
- Author
-
Land EJ, Perona A, Ramsden CA, and Riley PA
- Subjects
- Amides chemistry, Amidines chemistry, Dopamine chemistry, Drug Stability, Guanidine chemistry, Structure-Activity Relationship, Dopamine analogs & derivatives
- Abstract
The influence of N-substituents on the mode of reaction of ortho-quinones generated by oxidation of N-substituted dopamine derivatives has been studied. Ortho-quinones with amide, urea or guanidine side chains are relatively stable, with evidence of rearrangement to para-quinomethanes. The N-methylthiourea derivative rapidly cyclises giving a bicyclic product . The trichloromethylamidine derivative also rapidly cyclises but in this case gives a spirocyclic derivative . In contrast to the transient formation of spirocyclic products by other ortho-quinones derived from dopamine derivatives, e.g., , the product is stable and has been isolated and fully characterised.
- Published
- 2009
- Full Text
- View/download PDF
46. Evidence consistent with the requirement of cresolase activity for suicide inactivation of tyrosinase.
- Author
-
Land EJ, Ramsden CA, Riley PA, and Stratford MR
- Subjects
- Catalysis, Catechols chemistry, Catechols metabolism, Enzyme Activation, Kinetics, Oxidation-Reduction, Oxygen metabolism, Resorcinols metabolism, Agaricus enzymology, Monophenol Monooxygenase metabolism, Musa enzymology
- Abstract
Tyrosinase is a mono-oxygenase with a dinuclear copper catalytic center which is able to catalyze both the ortho-hydroxylation of monophenols (cresolase activity) and the oxidation of catechols (catecholase activity) yielding ortho-quinone products. Tyrosinases appear to have arisen early in evolution and are widespread in living organisms where they are involved in several processes, including antibiosis, adhesion of molluscs, the hardening of the exoskeleton of insects, and pigmentation. Tyrosinase is the principal enzyme of melanin formation in vertebrates and is of clinical interest because of the possible utilization of its activity for targeted treatment of malignant melanoma. Tyrosinase is characterised by an irreversible inactivation that occurs during the oxidation of catechols. In a recent publication we proposed a mechanism to account for this feature based on the ortho-hydroxylation of catecholic substrates, during which process Cu(II) is reduced to Cu(0) which no longer binds to the enzyme and is eliminated (reductive elimination). Since this process is dependent on cresolase activity of tyrosinase, a strong prediction of the proposed inactivation mechanism is that it will not be exhibited by enzymes lacking cresolase activity. We show that the catechol oxidase readily extracted from bananas (Musa cavendishii) is devoid of cresolase activity and that the kinetics of catechol oxidation do not exhibit inactivation. We also show that a species with the molecular mass of the putative cresolase oxidation product is formed during tyrosinase oxidation of 4-methylcatechol. The results presented are entirely consistent with our proposed mechanism to account for suicide-inactivation of tyrosinase.
- Published
- 2008
- Full Text
- View/download PDF
47. The mechanism of suicide-inactivation of tyrosinase: a substrate structure investigation.
- Author
-
Land EJ, Ramsden CA, and Riley PA
- Subjects
- Binding Sites, Catechols chemistry, Catechols metabolism, Molecular Structure, Oxidation-Reduction, Phenols chemistry, Phenols metabolism, Structure-Activity Relationship, Monophenol Monooxygenase antagonists & inhibitors, Monophenol Monooxygenase chemistry, Monophenol Monooxygenase metabolism, Phenol chemistry, Phenol metabolism, Protein Structure, Tertiary
- Abstract
Tyrosinase is a copper-containing mono-oxygenase, widely distributed in nature, able to catalyze the oxidation of both phenols and catechols to the corresponding ortho-quinones. Tyrosinase is characterised by a hitherto unexplained irreversible inactivation which occurs during the oxidation of catechols. Although the corresponding catechols are formed during tyrosinase oxidation of monophenols, inactivation in the presence of monophenolic substrates is minimal. Previous studies have established the kinetic features of the inactivation reaction which is first-order in respect of the enzyme concentration. The inactivation reaction exhibits the same pH-profile and saturation properties as the oxidation reaction, classing the process as a mechanism-based suicide inactivation. The recent elucidation of the crystallographic structure of tyrosinase has stimulated a new approach to this long-standing enigma. Here we report the results of an investigation of the tyrosinase-catalysed oxidation of a range of hydroxybenzenes which establish the structural requirements associated with inactivation. We present evidence for an inactivation mechanism based on catechol hydroxylation, with loss of one of the copper atoms at the active site. The inactivation mechanism involves two linked processes occurring in situ: (a) catechol presentation resulting in alpha-oxidation, and (b) deprotonation of an adjacent group. On the basis of our experimental data we believe that a similar mechanism may account for the inhibitory action of resorcinols.
- Published
- 2007
- Full Text
- View/download PDF
48. An outbreak of wound infection in cardiac surgery patients caused by Enterobacter cloacae arising from cardioplegia ice.
- Author
-
Breathnach AS, Riley PA, Shad S, Jownally SM, Law R, Chin PC, Kaufmann ME, and Smith EJ
- Subjects
- Cardiovascular Surgical Procedures adverse effects, Cross Infection etiology, Cross Infection prevention & control, DNA, Bacterial analysis, Enterobacter cloacae genetics, Enterobacter cloacae isolation & purification, Enterobacteriaceae Infections etiology, Enterobacteriaceae Infections prevention & control, Hospital Units, Humans, Infection Control, London epidemiology, Postoperative Complications, Sternum, Surgical Wound Infection etiology, Surgical Wound Infection prevention & control, Cross Infection epidemiology, Disease Outbreaks, Enterobacteriaceae Infections epidemiology, Surgical Wound Infection epidemiology
- Abstract
This paper describes an outbreak of postoperative sternal wound infections. A cardiac surgeon noted a cluster of serious infections leading to wound dehiscence, despite the fact that none of his colleagues had noticed a rise in infection rates. The infections were predominantly with Enterobacter cloacae, and molecular typing and serotyping showed these isolates to be indistinguishable. Observation of the surgeon's practice revealed nothing untoward, and there were no infections among his patients operated on in another hospital. There appeared to be no significant difference between the modes of operation of the different surgeons. The operating theatres were screened to exclude an environmental source, with samples cultured on CHROMagar Orientation, a selective/differential medium designed for urine samples. Further questioning revealed one difference between the practices of the different surgeons; this surgeon used semi-frozen Hartmann's solution to achieve cardioplegia. The freezer used for this was swabbed and yielded E. cloacae, indistinguishable from the clinical isolates. It is hypothesized that this organism contaminated the freezer, and that the contamination was passed on to the ice/slush solution, thus infecting the patients. There have been no more cases since the freezer was replaced, a rigorous cleaning schedule instituted, and steps taken to reduce the possibility of any further contamination.
- Published
- 2006
- Full Text
- View/download PDF
49. Dopaquinone redox exchange with dihydroxyindole and dihydroxyindole carboxylic acid.
- Author
-
Edge R, d'Ischia M, Land EJ, Napolitano A, Navaratnam S, Panzella L, Pezzella A, Ramsden CA, and Riley PA
- Subjects
- Kinetics, Oxidation-Reduction, Computer Simulation, Free Radicals chemistry, Indoles chemistry, Models, Chemical
- Abstract
A pulse radiolytic investigation has been conducted to establish whether a redox reaction takes place between dopaquinone and 5,6-dihydroxyindole (DHI) and its 2-carboxylic acid (DHICA) and to measure the rate constants of the interactions. To obviate possible confounding reactions, such as nucleophilic addition, the method employed to generate dopaquinone used the dibromide radical anion acting on dopa to form the semiquinone which rapidly disproportionates to dopaquinone. In the presence of DHI the corresponding indole-5,6-quinone (and/or tautomers) was also formed directly but, by judicious selection of suitable relative concentrations of initial reactants, we were able to detect the formation of additional indolequinone from the redox exchange reaction of DHI with dopaquinone which exhibited a linear dependency on the concentration of DHI. Computer simulation of the experimental time profiles of the absorption changes showed that, under the conditions chosen, redox exchange does proceed but not quite to completion, a forward rate constant of 1.4 x 10(6)/M/s being obtained. This is in the same range as the rate constants previously established for reactions of dopaquinone with cyclodopa and cysteinyldopa. In similar experiments carried out with DHICA, the reaction more obviously does not go to completion and is much slower, k (forward) =1.6 x 10(5)/M/s. We conclude that, in the eumelanogenic pathway, DHI oxidation may take place by redox exchange with dopaquinone, although such a reaction is likely to be less efficient for DHICA.
- Published
- 2006
- Full Text
- View/download PDF
50. Mechanistic studies of melanogenesis: the influence of N-substitution on dopamine quinone cyclization.
- Author
-
Borovansky J, Edge R, Land EJ, Navaratnam S, Pavel S, Ramsden CA, Riley PA, and Smit NP
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Dopamine chemistry, Isomerism, Melanins chemistry, Melanoma drug therapy, Melanoma enzymology, Molecular Structure, Neoplasm Proteins chemistry, Oxidation-Reduction, Prodrugs chemistry, Agaricus enzymology, Dopamine analogs & derivatives, Fungal Proteins chemistry, Melanins chemical synthesis, Monophenol Monooxygenase chemistry
- Abstract
The influence of side-chain structure on the mode of reaction of ortho-quinone amines has been investigated with a view, ultimately, to developing potential methods of therapeutic intervention by manipulating the early stages of melanogenesis. Four N-substituted dopamine derivatives have been prepared and quinone formation studied using pulse radiolysis and tyrosinase-oximetry. Ortho-quinones with an amide or urea side chain were relatively stable, although evidence for slow formation of isomeric para-quinomethanes was observed. A thiourea derivative cyclized fairly rapidly (k = 1.7/s) to a product containing a seven-membered ring, whereas a related amidine gave more rapidly (k approximately 2.5 x 10(2)/s) a stable spirocyclic product. The results suggest that cyclization of amides, ureas and carbamates (NHCO-X; X = R, NHR or OR) does not occur and is not, therefore, a viable approach to the formation of tyrosinase-activated antimelanoma prodrugs. It is also concluded that for N-acetyldopamine spontaneous ortho-quinone to para-quinomethane isomerization is slow.
- Published
- 2006
- Full Text
- View/download PDF
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