67 results on '"Lisa A. Marshall"'
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2. Application of ultrasound-assisted extraction method to recover betalains and polyphenols from red beetroot waste
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Lisa J. Marshall, Ganwarige Sumali N Fernando, Natalia N. Sergeeva, Emmanouil H. Papaioannou, Kelly Wood, and Christine Bosch
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Antioxidant ,Renewable Energy, Sustainability and the Environment ,Chemistry ,General Chemical Engineering ,medicine.medical_treatment ,Pulp (paper) ,Extraction (chemistry) ,food and beverages ,General Chemistry ,engineering.material ,Solvent ,chemistry.chemical_compound ,Pigment ,Polyphenol ,Betalain ,visual_art ,medicine ,engineering ,visual_art.visual_art_medium ,Environmental Chemistry ,Food science ,Beet pulp - Abstract
Agriculture and food industries generate substantial quantities of waste material with a huge potential for bioactive ingredients to be recovered and converted into high-value chemicals. Red beetroot, known for its high content in betalains, natural red pigments, as well as polyphenols, fiber, and nitrate, is experiencing increasing demand, in particular as juice, which is leaving behind large amounts of waste. The present study focused on the recovery of betalains and polyphenols from dried whole beetroot and wet and dried beet pulp waste from the juicing industry. As part of an ultrasound-assisted extraction, ethanol/water-based solvent mixtures were used as they were found to be more effective than single solvents. Enzyme-assisted extraction was initially examined in the case of wet pulp but was not able to retain betalains. Betalains appear to be more stable in dried pulp. Ultrasound-assisted extraction was found to be more suitable to effectively extract both betalains and polyphenols with a high bioactive yield from dried pulp. The total betalain and polyphenol profiles as well as storage stability and antioxidant capacities were evaluated over a period of four weeks after extraction from the dried waste. During the four-week storage, betalains quickly degraded at room temperature in contrast to −20 °C, whereas polyphenols and antioxidative activity were much less influenced by temperature. When compared, dried samples from the beetroot juicing industry demonstrate good betalain and polyphenol extractability; thus, these data indicate that dried beet waste can serve as a good source of betalains for the color industry and other technological sectors.
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- 2021
3. Relationships, experience, and support: staff perception of safety in a forensic mental health facility
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Lisa A. Marshall, Melanie I. Stuckey, and Emma A. Adams
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Focus (computing) ,medicine.medical_specialty ,Aggression ,media_common.quotation_subject ,05 social sciences ,Mental illness ,medicine.disease ,Mental health ,Forensic science ,Psychiatry and Mental health ,Clinical Psychology ,Perception ,050501 criminology ,medicine ,ComputingMilieux_COMPUTERSANDSOCIETY ,medicine.symptom ,Psychology ,Psychiatry ,0505 law ,Qualitative research ,media_common - Abstract
Safety is a primary focus in forensic mental health facilities as aggression and violence related to symptoms of mental illness is an ongoing challenge in these settings. Recovery-oriented strategi...
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- 2019
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4. Tumors establish resistance to immunotherapy by regulating Treg recruitment via CCR4
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Omar Robles, Sachie Marubayashi, Brian Wong, Angela Wadsworth, Paul D. Kassner, Lisa A. Marshall, Gene Cutler, David J. Wustrow, Jerick Sanchez, David Chian, Martin Brovarney, Jeffrey J. Jackson, Dirk G. Brockstedt, Oezcan Talay, Scott Jacobson, Mikhail Zibinsky, Aparna Jorapur, Deepa Pookot, and Hu Dennis X
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Immunology ,CCR4 ,chemical and pharmacologic phenomena ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunology and Allergy ,Medicine ,RC254-282 ,Pharmacology ,Tumor microenvironment ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,030104 developmental biology ,Oncology ,Tumor Escape ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,business ,CC chemokine receptors ,CCL22 - Abstract
BackgroundCheckpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (Treg) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of Treg is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human Treg express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of Treg into the tumor microenvironment (TME).MethodsWe developed in vitro and in vivo models to assess Treg migration and antitumor efficacy using a potent and selective CCR4 antagonist, CCR4-351. We used two separate tumor models, Pan02 and CT26 mouse tumors, that have high and low CCR4 ligand expression, respectively. Tumor growth inhibition as well as the frequency of tumor-infiltrating Treg and effector T cells was assessed following the treatment with CCR4 antagonist alone or in combination with CPI.ResultsUsing a selective and highly potent, novel small molecule inhibitor of CCR4, we demonstrate that migration of CCR4+ Treg into the tumor drives tumor progression and resistance to CPI treatment. In tumor models with high baseline levels of CCR4 ligands, blockade of CCR4 reduced the number of Treg and enhanced antitumor immune activity. Notably, in tumor models with low baseline level of CCR4 ligands, treatment with immune CPIs resulted in significant increases of CCR4 ligands and Treg numbers. Inhibition of CCR4 reduced Treg frequency and potentiated the antitumor effects of CPIs.ConclusionTaken together, we demonstrate that CCR4-dependent Treg recruitment into the tumor is an important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of Treg and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer.Statement of significanceCPI upregulates CCL17 and CCL22 expression in tumors and increases Treg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits Treg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligandhigh tumors or in combination with CPIs in CCR4 ligandlow tumors.
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- 2020
5. The role of gastric emptying in β-carotene absorption during simulated in vitro digestion
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Ng'andwe Kalungwana, Lisa J. Marshall, Christine Bosch, and Alan Mackie
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Nutrition and Dietetics ,Chromatography ,Gastric emptying ,Chemistry ,medicine.medical_treatment ,digestive, oral, and skin physiology ,Carotene ,medicine ,Medicine (miscellaneous) ,In vitro digestion ,Absorption (electromagnetic radiation) - Abstract
IntroductionThe availability of β-carotene from provitamin A rich foods in order to improve the provision of vitamin A in humans through food-based approaches is an important factor in mitigating micronutrient deficiencies. However, the extent of intestinal absorption (and subsequent availability of carotenoids to target tissues) is dependent on meal preparation, components of the meal and other intrinsic factors during gastro-intestinal (GI) digestion. Gastric emptying (GE), dictated by the caloric value of a meal, has been suggested as a critical component in determining β-carotene absorption. Indeed, dietary intake of high energy meals may just unravel the underlying factors associated with low uptake of dietary carotenoids during digestion. While several studies have reported the uptake of β-carotene as an individual pure compound under different digestive conditions(1), very few studies have assessed the effects of dietary carotenoids embedded in an energy dense meal, as would normally be consumed, on GI transit time and subsequent nutrient release.Materials and MethodsIn this study, we investigated the role of meal composition, particularly its caloric value, in modulating gastric emptying and thus the absorption of β-carotene. A step-by-step in vitro semi-dynamic model that simulates adult gastric digestion(2) was used on a prepared standard meal whose caloric value was estimated based on the Atwater system as described elsewhere with the assumption that the caloric density of the meal will assume a linear GE rate of 2kcal/min.ResultsPreliminary results indicate that, short transit times of 40 minutes, mimicking early GE, have the highest concentration (3.84 ± 0.014; Mean SD) and therefore, highest bioaccessibility (55.7%) compared to the longer transit time of 160 minutes (0.81 ± 0.002; Mean SD) and (11.8%) for β-carotene concentration and bioaccessibility from a standard meal, respectively.DiscussionThe results suggest that gastric behaviour of the food determines the kinetics of bioaccessibility that may not result in low β-carotene release and ultimately low bioaccessibility from the embedded matrix.
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- 2020
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6. A prospective study of pathways to hospital readmission in Canadian forensic psychiatric patients
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Lisa A. Marshall, Stephanie R. Penney, and Alexander I. F. Simpson
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Hospital readmission ,business.industry ,05 social sciences ,Context (language use) ,medicine.disease ,030227 psychiatry ,Forensic science ,03 medical and health sciences ,Psychiatry and Mental health ,Clinical Psychology ,0302 clinical medicine ,050501 criminology ,medicine ,Medical emergency ,Substance use ,Violence risk ,Prospective cohort study ,business ,0505 law - Abstract
Individuals admitted to secure care often experience lengthy hospitalizations and are likely to be admitted on more than one occasion. In the context of growing demand and costs associated with sec...
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- 2017
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7. Effect of thermal treatment and storage on bioactive compounds, organic acids and antioxidant activity of baobab fruit (Adansonia digitata) pulp from Malawi
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Lisa J. Marshall, David T. Tembo, and Melvin Holmes
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0301 basic medicine ,030109 nutrition & dietetics ,Antioxidant ,ABTS ,biology ,Vitamin C ,Chemistry ,DPPH ,Pulp (paper) ,medicine.medical_treatment ,04 agricultural and veterinary sciences ,engineering.material ,biology.organism_classification ,040401 food science ,03 medical and health sciences ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Botany ,engineering ,medicine ,Food science ,Gallic acid ,Adansonia digitata ,Procyanidin B2 ,Food Science - Abstract
Bioactive compounds of baobab (Adansonia digitata) pulp from Malawi were investigated. The effect of thermal treatment and storage on selected quality attributes of the juice was also evaluated. Organic compounds were analysed by HPLC; total phenol content (TPC) and total antioxidant activity (FRAP, ABTS and DPPH) were measured by spectrophotometry. Malawi baobab pulp contains high levels of procyanidin B2 (533 ± 22.6 mg/100 g FW), vitamin C (AA + DHA) (466 ± 2.5 mg/100 g FW), gallic acid (68.5 ± 12.4 mg/100 g FW) and (−)-epicatechin (43.0 ± 3.0 mg/100 g FW) and showed a maximum TPC of 1.89 × 103 ± 1.61 mg GAE/100 g FW. The maximum antioxidant activity was 2.81 × 103 ± 92.8 mg TEAC/100 g FW for FRAP, 1.52 × 103 ± 17.1 mg TEAC/100 g FW for ABTS and 50.9 ± 0.43% DPPH for DPPH. Thermal pasteurisation (72 °C, 15 s) retained vitamin C which further showed extended half-life under refrigeration temperature (6 °C). Procyanidin B2, (−)-epicatechin, TPC and antioxidant activity fluctuated during storage. Antioxidant activity was significantly correlated (p ≤ 0.05) with bioactive compounds and TPC.
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- 2017
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8. A Dietary Intervention of Bioactive Enriched Foods Aimed at Adults at Risk of Metabolic Syndrome: Protocol and Results from PATHWAY-27 Pilot Study
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S. Sutulic, Luigi Ricciardiello, Julien Amat, Melvin Holmes, Mattia Di Nunzio, Corinne Malpuech-Brugère, Marynka Ulaszewska, Achim Bub, Alice Arianna, Stephanie N. Seifert, Lisa J. Marshall, Alessandra Bordoni, Caroline Orfila, Imola Nemeth, Zsófia Kertész, A. Blot, Department of Physiology and Biochemistry of Nutrition, Max-Planck-Institut, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Nutrition Humaine, School of Food Science and Nutrition, University of Leeds, CHU Clermont-Ferrand, Department of Agri-Food Sciences and Technologies (DISTAL), Università di Bologna, Campden BRI Hungary Ltd, AdWare Research Ltd, Department of Medical and Surgical Sciences, Universita degli Studi di Padova, Dipartimento Qualità Alimentare e Nutrizione, Centro Ricerca ed Innovazione-Fondazione Edmund Mach, European Commission under the Seventh Framework Programme 311876, Bub, Achim, Malpuech-Brugère, Corinne, Orfila, Caroline, Amat, Julien, Arianna, Alice, Blot, Adeline, Di Nunzio, Mattia, Holmes, Melvin, Kertész, Zsófia, Marshall, Lisa, Nemeth, Imola, Ricciardiello, Luigi, Seifert, Stephanie, Sutulic, Samantha, Ulaszewska, Marynka, Bordoni, Alessandra, Max Planck Institute, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Clermont-Ferrand, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Università degli Studi di Padova = University of Padua (Unipd), and Orfila, C.
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0301 basic medicine ,Male ,Pilot Projects ,nutritional intervention trials ,anthocyanin ,functional food ,0302 clinical medicine ,anthocyanins ,bakery ,bioactive ,dairy ,docosahexaenoic acid ,egg ,metabolic syndrome ,oat beta-glucan ,short chain fatty acid ,ddc:796 ,2. Zero hunger ,Nutrition and Dietetics ,Fatty Acids ,docosahexaenoic ,Short chain fatty acids ,Middle Aged ,3. Good health ,Athletic & outdoor sports & games ,Docosahexaenoic acid ,Alimentation et Nutrition ,Food, Fortified ,Female ,acid ,lcsh:Nutrition. Foods and food supply ,nutritional intervention trial ,Adult ,medicine.medical_specialty ,Enriched Food ,030209 endocrinology & metabolism ,lcsh:TX341-641 ,Placebo ,Article ,03 medical and health sciences ,Functional food ,Double-Blind Method ,Internal medicine ,Diabetes mellitus ,Intervention (counseling) ,medicine ,Food and Nutrition ,Humans ,Settore CHIM/10 - CHIMICA DEGLI ALIMENTI ,Adverse effect ,Aged ,030109 nutrition & dietetics ,business.industry ,medicine.disease ,Diet ,Metabolic syndrome ,business ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,Food Science - Abstract
This article belongs to the Special Issue Dietary Bioactives and Human Health; Around a quarter of the global adult population have metabolic syndrome (MetS) and therefore increased risk of cardiovascular mortality and diabetes. Docosahexaenoic acid, oat beta-glucan and grape anthocyanins have been shown to be effective in reducing MetS risk factors when administered as isolated compounds, but their effect when administered as bioactive-enriched foods has not been evaluated. OBJECTIVE: The overall aim of the PATHWAY-27 project was to evaluate the effectiveness of bioactive-enriched food consumption on improving risk factors of MetS. A pilot study was conducted to assess which of five bioactive combinations provided within three different food matrices (bakery, dairy or egg) were the most effective in adult volunteers. The trial also evaluated the feasibility of production, consumer acceptability and gastrointestinal tolerance of the bioactive-enriched food. METHOD: The study included three monocentric, parallel-arm, double-blind, randomised, dietary intervention trials without a placebo. Each recruiting centre tested the five bioactive combinations within a single food matrix. RESULTS: The study was completed by 167 participants (74 male, 93 female). The results indicated that specific bioactive/matrix combinations have effects on serum triglyceride or HDL-cholesterol level without adverse effects. CONCLUSION: The study evidenced that bioactive-enriched food offers a promising food-based strategy for MetS prevention, and highlighted the importance of conducting pilot studies.
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- 2019
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9. The assessment of dynamic risk among forensic psychiatric patients transitioning to the community
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Lisa A. Marshall, Stephanie R. Penney, and Alexander I. F. Simpson
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Predictive validity ,medicine.medical_specialty ,Population ,PsycINFO ,Violence ,Risk Assessment ,Arts and Humanities (miscellaneous) ,Risk Factors ,medicine ,Humans ,Prospective Studies ,Psychiatry ,education ,Prospective cohort study ,Crime Victims ,General Psychology ,0505 law ,education.field_of_study ,05 social sciences ,Hazard ratio ,medicine.disease ,Mental illness ,Psychiatry and Mental health ,Psychotic Disorders ,Mood disorders ,050501 criminology ,Risk assessment ,Psychology ,Law ,Clinical psychology - Abstract
Individuals with serious mental illness (SMI; i.e., psychotic or major mood disorders) are vulnerable to experiencing multiple forms of adverse safety events in community settings, including violence perpetration and victimization. This study investigates the predictive validity and clinical utility of modifiable risk factors for violence in a sample of 87 forensic psychiatric patients found Not Criminally Responsible on Account of Mental Disorder (NCRMD) transitioning to the community. Using a repeated-measures prospective design, we assessed theoretically based dynamic risk factors (e.g., insight, psychiatric symptoms, negative affect, treatment compliance) before hospital discharge, and at 1 and 6 months postdischarge. Adverse outcomes relevant to this population (e.g., violence, victimization, hospital readmission) were measured at each community follow-up, and at 12 months postdischarge. The base rate of violence (23%) was similar to prior studies of discharged psychiatric patients, but results also highlighted elevated rates of victimization (29%) and hospital readmission (28%) characterizing this sample. Many of the dynamic risk indicators exhibited significant change across time and this change was related to clinically relevant outcomes. Specifically, while controlling for baseline level of risk, fluctuations in dynamic risk factors predicted the likelihood of violence and hospital readmission most consistently (hazard ratios [HR] = 1.35-1.84). Results provide direct support for the utility of dynamic factors in the assessment of violence risk and other adverse community outcomes, and emphasize the importance of incorporating time-sensitive methodologies into predictive models examining dynamic risk. (PsycINFO Database Record
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- 2016
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10. Codon-dependent noise dictates cell-to-cell variability in nutrient poor environments
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Philippe Cluzel, Enrique Balleza, J. Mark Kim, and Lisa F. Marshall
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chemistry.chemical_classification ,biology ,Cell ,biology.organism_classification ,Amino acid ,Nutrient ,medicine.anatomical_structure ,chemistry ,Transcription (biology) ,Transfer RNA ,Biophysics ,medicine ,Intracellular ,TRNA Charging ,Bacteria - Abstract
Under nutrient-rich conditions, stochasticity of transcription drives protein expression noise. However, by shifting the environment to amino acid-limited conditions, we identified in E. coli a source of noise whose strength is dictated by translational processes. Specifically, we discovered that cell-to-cell variations in fluorescent protein expression depend on codon choice, with codons yielding lower mean expression after amino acid downshift also resulting in greater noise. We propose that ultra-sensitivity in the tRNA charging/discharging cycle shapes the strength of the observed noise by amplifying fluctuations in global intracellular parameters, such as the concentrations of amino acid, synthetase, and tRNA. We hypothesize that this codon-dependent noise may allow bacteria to selectively optimize cell-to-cell variability in poor environments without relying on low molecular numbers.
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- 2018
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11. Co-creation of the Safewards Model in a Forensic Mental Health Care Facility
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Sarah Kipping, Jen L De Souza, and Lisa A Marshall
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Behavior Control ,Mental Health Services ,Canada ,Attitude of Health Personnel ,MEDLINE ,Psychiatric Nursing ,Psychiatric Department, Hospital ,Behavior control ,Security Measures ,Conflict, Psychological ,03 medical and health sciences ,0302 clinical medicine ,Nursing ,medicine ,Co-creation ,Humans ,Models, Nursing ,Complex problems ,030504 nursing ,Aggression ,030227 psychiatry ,Mental health care ,Pshychiatric Mental Health ,medicine.symptom ,0305 other medical science ,Psychology - Abstract
Violence and aggression are highly complex problems in mental health care facilities; thus, multi-faceted conflict-reduction strategies are required to mitigate and reduce violence. Safewards is an evidence-informed model aimed at preventing events that have the capacity to trigger aggression and violence. Effectiveness studies of the implementation of Safewards have shown mixed results, including that implementation strategies failed to engage staff and fidelity was low. The objective of this study was to examine the effectiveness of implementing the Safewards model with an approach that embedded co-creation principles in the staff training. Overall, results showed high staff engagement. The average rate of attendance at the classroom-based, staff champion training (n = 108) was 79% (SD = 23). Additionally, online training modules were available to all staff and were completed by 238 of 259 forensic program staff (92%). Overall, staff perceived co-creation to be a positive strategy; staff liked being asked to be involved in the planning, felt that their voices were heard, and believed that it contributed to the success of the Safewards implementation. This study showed that the inclusion of co-creation principles in the implementation strategy enhanced staff adherence to the Safewards model as demonstrated by the high fidelity scores, and effectively led to increased buy-in and engagement of staff.
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- 2018
12. Modulation of the orthostatic blood pressure response by acute nitrate consumption is dependent upon ethnic origin
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Lisa J. Marshall, Katie M. Chuter, Katie Allen, Katherine Fithon, and David Hauton
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0301 basic medicine ,Tachycardia ,Male ,medicine.medical_specialty ,Supine position ,Physiology ,Blood Pressure ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Electrocardiography ,Young Adult ,0302 clinical medicine ,Heart Rate ,Physiology (medical) ,Internal medicine ,Heart rate ,medicine ,Ethnicity ,Heart rate variability ,Humans ,Pharmacology ,Autonomic nerve ,Nitrates ,business.industry ,Pulse pressure ,Autonomic nervous system ,030104 developmental biology ,Endocrinology ,Blood pressure ,Female ,medicine.symptom ,business - Abstract
Orthostatic stress triggers a response to maintain cerebral perfusion and prevent syncope. Given the hypotensive effects of inorganic nitrate this response to orthostasis may be altered by acute supplementation with inorganic nitrate and modified by ethnic origin. Caucasian and SE Asian (n = 30 for both), were recruited and subjected to an ‘active stand test’ and brachial artery blood pressure (BP), digit blood flow and ECG were recorded. Following inorganic nitrate supplementation, (10 mg/kg body mass) the tests were repeated. For both Caucasian and SE Asians transition to standing increased diastolic pressure (DP) and heart rate (HR) (P < 0.001 for both) and by calculation increased rate‐pressure product (P < 0.001) and decreased pulse pressure (P < 0.01 for both) indicative of decreased ventricular filling. Nitrate supplementation decreased both DP (P < 0.001) and HR (P < 0.001). Assessment of HR variability suggested sympathetic nerve activity, was higher throughout in Caucasians (P < 0.05) coupled with higher parasympathetic tone (P < 0.01). Nitrate had no effect on cardiac autonomic nerve activity, as estimated using HR variability, for supine or standing subjects. The tachycardia and hypertension associated with orthostatic stress were preserved in both Caucasian and SE Asian subjects, however, we highlight possible differences in autonomic nervous system activity between Caucasians and SE Asians. SE Asians are resistant to the hypotensive effects of inorganic nitrate supplementation suggesting the absence of a crucial mechanism for activation of the nitrate‐nitrite‐nitric oxide system.
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- 2018
13. Feasibility of SaeboFlex Upper-limb Training in Acute Stroke Rehabilitation: A Clinical Case Series
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Ramachandran Sivakumar, Lisa M. Marshall, and Rebecca A. Stuck
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Occupational therapy ,Weakness ,medicine.medical_specialty ,Rehabilitation ,business.industry ,medicine.medical_treatment ,General Medicine ,medicine.disease ,law.invention ,medicine.anatomical_structure ,Physical medicine and rehabilitation ,Occupational Therapy ,Randomized controlled trial ,law ,Test score ,Patient experience ,Physical therapy ,Medicine ,Upper limb ,medicine.symptom ,business ,Stroke - Abstract
Upper-limb (UL) recovery following stroke is often poor. UL rehabilitation therefore continues to be a major focus for occupational therapy. Published evidence for the effectiveness of SaeboFlex training in acute stroke rehabilitation is scarce. The purpose of this study is to explore the feasibility and patient experience of SaeboFlex training in acute stroke. This feasibility study recruited stroke patients (
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- 2014
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14. The predictive validity of the HCR-20 following clinical implementation: does it work in practice?
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Lindsay Thomson, Gabriele Vojt, and Lisa A. Marshall
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Predictive validity ,medicine.medical_specialty ,business.industry ,medicine.disease ,Personality disorders ,Psychiatry and Mental health ,Clinical Psychology ,Forensic psychiatry ,Scale (social sciences) ,Cohort ,medicine ,Risk assessment ,Psychiatry ,Prospective cohort study ,Psychology ,business ,Risk management ,Clinical psychology - Abstract
This prospective study describes the predictive validity of the Historical Clinical Risk Management-20 Scale (HCR-20) when applied to clinical practice among 109 male mentally disordered offenders in a high secure forensic hospital. Data on violent incidents including reconvictions were collected from multiple sources. The results imply that the implemented HCR-20s did not predict future violence regardless of setting (community vs inpatient) nor time (short vs long term) except for serious incidents. This may indicate that the implemented HCR-20s informed risk management through systematic tailoring of care and treatment plans. Evidence supporting this interpretation was found in a reduction in violent incidents and offending when compared to an earlier study with a similar cohort. Alternatively, the completion of a violence risk assessment by clinicians rather than researchers may have affected the quality of completed assessments. Further research is required to better understand the complex mechanisms...
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- 2013
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15. Effects of a 4-week intervention with ready-made bioactive enriched pancakes on biomarkers of the metabolic syndrome
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M. Muller, Alessandra Bordoni, S. Sutulic, C. Bösch, Caroline Orfila, Lisa J. Marshall, and H. Hingyi
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medicine.medical_specialty ,Nutrition and Dietetics ,business.industry ,Intervention (counseling) ,Internal medicine ,medicine ,Medicine (miscellaneous) ,Metabolic syndrome ,medicine.disease ,business - Published
- 2016
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16. Intraoperative detection and removal of microscopic residual sarcoma using wide-field imaging
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Moungi G. Bawendi, Shalini Ramasunder, Rebecca D. Dodd, Jeffrey K. Mito, Jessica E. Carter, Chang-Lung Lee, Linda G. Griffith, Jorge Ferrer, David G. Kirsch, Kyle C. Cuneo, Yongbaek Kim, Lisa F. Marshall, Brian E. Brigman, W. David Lee, and William C. Eward
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Cancer Research ,medicine.medical_specialty ,Pathology ,Soft Tissue Neoplasm ,intraoperative imaging ,Neoplasm, Residual ,Infrared Rays ,Soft Tissue Neoplasms ,Residual ,Intraoperative Period ,Mice ,medicine ,Animals ,Fluorescent Dyes ,business.industry ,Soft tissue sarcoma ,optical molecular imaging ,Cancer ,Sarcoma ,Original Articles ,medicine.disease ,Oncology ,cathepsin proteases ,Surgery, Computer-Assisted ,soft tissue sarcoma ,Radiology ,Sarcoma, Experimental ,Molecular imaging ,business ,Preclinical imaging - Abstract
BACKGROUND: The goal of limb-sparing surgery for a soft tissue sarcoma of the extremity is to remove all malignant cells while preserving limb function. After initial surgery, microscopic residual disease in the tumor bed will cause a local recurrence in approximately 33% of patients with sarcoma. To help identify these patients, the authors developed an in vivo imaging system to investigate the suitability of molecular imaging for intraoperative visualization. METHODS: A primary mouse model of soft tissue sarcoma and a wide field-of-view imaging device were used to investigate a series of exogenously administered, near-infrared (NIR) fluorescent probes activated by cathepsin proteases for real-time intraoperative imaging. RESULTS: The authors demonstrated that exogenously administered cathepsin-activated probes can be used for image-guided surgery to identify microscopic residual NIR fluorescence in the tumor beds of mice. The presence of residual NIR fluorescence was correlated with microscopic residual sarcoma and local recurrence. The removal of residual NIR fluorescence improved local control. CONCLUSIONS: The authors concluded that their technique has the potential to be used for intraoperative image-guided surgery to identify microscopic residual disease in patients with cancer. Cancer 2012. © 2012 American Cancer Society.
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- 2012
17. The clinical reality of implementing formal risk assessment and management measures within high secure forensic care
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Morag Slesser, Lindsay Thomson, Gabriele Vojt, and Lisa A. Marshall
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Adult ,Hospitals, Psychiatric ,Male ,Risk management plan ,Process management ,Process (engineering) ,Poison control ,Violence ,Risk Assessment ,Documentation ,Humans ,Medicine ,Risk management ,Patient Care Team ,business.industry ,Mental Disorders ,Health Policy ,Human factors and ergonomics ,medicine.disease ,United Kingdom ,IT risk management ,Issues, ethics and legal aspects ,Female ,Medical emergency ,business ,Risk assessment ,Law - Abstract
This paper describes the successful implementation of a formal violence risk assessment and management strategy within a high secure forensic care facility. The aim of the implementation was to ensure that each patient had a formal violence risk assessment and management plan that was shared and applied to clinical practice by the patient's clinical team. The process as a whole, from risk assessment to risk management including appropriate care and treatment documentation, is outlined. In this way, this paper also describes the difficulties and problems encountered within the organizational reality of implementation projects. Suggestions and recommendations on how to avoid and manage these are made.
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- 2011
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18. The assessment of imminent inpatient aggression: a validation study of the DASA-IV in Scotland
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Lisa A. Marshall, Gabriele Vojt, and Lindsay Thomson
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medicine.medical_specialty ,Ecological validity ,Aggression ,Risk management tools ,Psychiatry and Mental health ,Clinical Psychology ,Juvenile delinquency ,medicine ,Predictive power ,Psychiatric hospital ,Risk factor ,medicine.symptom ,Situational ethics ,Psychology ,Psychiatry - Abstract
Inpatient aggression in psychiatric settings poses a serious management problem. This study reports the findings of a prospective pilot study on the Dynamic Appraisal of Situational Aggression – Inpatient Version (DASA-IV), a structured risk assessment tool for imminent aggression. The study was conducted in the State Hospital, the high secure psychiatric hospital for Scotland and Northern Ireland. The outcome data were aggressive incidents recorded on the Staff Observation Aggression Scale – Revised (SOAS-R) and incidents noted on the hospital's online recording tool. All measures were completed by nursing staff as part of their daily clinical routine to ensure ecological validity. The DASA-IV was found to be of moderate to good predictive power. Limitations and suggestions for further research are outlined, and the potential for implementation of the tool is discussed.
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- 2010
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19. Abstract 2915: Discovery and optimization of potent and selective inhibitors of USP7 to enhance anti-tumor immunity and target tumor growth
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Kyle Young, Jacob Bradley Schwarz, Delia Bradford, Michael Sun, Gene Cutler, Jenny McKinnell, David Chian, Cesar Meleza, Grant M. Shibuya, Silpa Suthram, Betty Abraham, Andrew Napper, Martin Brovarney, David J. Wustrow, Akinori Okano, Paul Leger, Leanne Peiser, Deepika Kaveri, Nick Shah, Xinping Han, Sherra Johnson, Deepa Pookot, Oezcan Talay, Sachie Marubayashi, Scott Jacobson, Berenger Biannic, Dennis X. Hu, Lavanya Adusumilli, Yamini M. Ohol, Jack Maung, Paul D. Kassner, Lisa A. Marshall, Angela Wadsworth, John M. Ketcham, Andrea Kim, and Payal Rana
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Cancer Research ,Tumor microenvironment ,biology ,Regulatory T cell ,Cell growth ,Chemistry ,FOXP3 ,medicine.anatomical_structure ,Immune system ,Oncology ,Cancer research ,medicine ,biology.protein ,PTEN ,Mdm2 ,Transcription factor - Abstract
USP7 is a deubiquitinase (DUB) that has attracted much attention recently due to its multiple roles in promoting cancer progression. By removal of ubiquitin from protein substrates, USP7 stabilizes oncogenes such as MDM2 and Myc, destabilizes and inactivates the key tumor suppressors p53 and PTEN, and imparts resistance to DNA-damaging chemotherapy by enhancing DNA repair responses. USP7 plays an important role in suppression of immune responses in the tumor microenvironment by stabilizing the transcription factor FOXP3 and thereby enhancing the suppressive function of regulatory T cells. Thus, inhibition of USP7 is an appealing therapeutic strategy because it has the potential to impact important oncology targets such as transcription factors that have been widely viewed as undruggable. We employed structure-based and other medicinal chemistry techniques to enable the design of potent and selective USP7 inhibitors. Using a high-throughput assay of DUB activity employing rhodamine-labeled ubiquitin, we optimized several series of reversible USP7 inhibitors to sub-100 pM potency and selectivity of >10,000-fold over all other DUBs. Cellular activity was demonstrated using a luciferase reporter gene assay of p53 activation, revealing compounds with EC50 values ranging down to 20 nM. To assess the role of USP7 inhibition in enhancement of immune responses, we determined relief of suppression of effector T cells in vitro. Effector T cells (CD8+) were co-cultured with regulatory T cells (CD4+ FOXP3+) and antigen-presenting cells for 4 days, after which CD8+ cell proliferation was determined by flow cytometry. Treatment with USP7 inhibitors during co-culture resulted in relief of regulatory T cell suppression of CD8+ cell proliferation. In vivo enhancement of immune responses was assessed in rodent models of inflammation and tumor growth. Direct effects on tumor cell growth and viability were explored by profiling cytotoxicity of USP7 inhibitors as single agents and in combination with chemotherapeutic agents in a broad range of cancer cell lines. In preparation for future clinical development, compounds were modified to obtain desirable in vitro and in vivo ADME and toxicity profiles. Following extensive pre-clinical optimization, we have in hand orally bioavailable compounds with high permeability, low clearance, and minimal off-target activity. Citation Format: Betty Abraham, Lavanya Adusumilli, Berenger Biannic, Delia Bradford, Martin Brovarney, David Chian, Gene Cutler, Xinping Han, Dennis Hu, Scott Jacobson, Sherra Johnson, Paul Kassner, Deepika Kaveri, John Ketcham, Andrea Kim, Paul Leger, Lisa Marshall, Sachie Marubayashi, Jack Maung, Jenny McKinnell, Cesar Meleza, Yamini Ohol, Akinori Okano, Leanne Peiser, Deepa Pookot, Payal Rana, Jacob Schwarz, Nick Shah, Grant Shibuya, Michael Sun, Silpa Suthram, Oezcan Talay, Angela Wadsworth, David Wustrow, Kyle Young, Andrew Napper. Discovery and optimization of potent and selective inhibitors of USP7 to enhance anti-tumor immunity and target tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2915.
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- 2018
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20. Abstract 4752: EBV associated tumors have increased regulatory T cell recruitment and are therefore a potential indication for treatment with potent and selective small molecule CCR4 antagonists
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Maureen Kay Reilly, John M. Ketcham, Omar Robles, Aparna Jorapur, Sachie Marubayashi, Silpa Suthram, Oezcan Talay, Jacob Bradley Schwarz, Berenger Biannic, Minna Bui, Gene Cutler, Paul D. Kassner, Lisa A. Marshall, Ashkaan Younai, Dennis X. Hu, and Scott Jacobson
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Cancer Research ,Tumor microenvironment ,business.industry ,Regulatory T cell ,T cell ,FOXP3 ,medicine.disease ,medicine.disease_cause ,Epstein–Barr virus ,Lymphoma ,medicine.anatomical_structure ,Oncology ,hemic and lymphatic diseases ,Cancer cell ,medicine ,Cancer research ,business ,CD8 - Abstract
We have performed experiments to test whether Epstein Barr Virus (EBV)-infected tumors are enhanced for regulatory T cell (Treg) infiltration and whether selective and potent CCR4 antagonists would be a particularly effective therapeutic in this class of indications. Treg cells, which contribute to an immune-suppressive tumor microenvironment (TME), are attracted to tumors via the recognition of CCL17 and CCL22 ligands by the CCR4 receptor. These chemokines have been shown to be expressed in cells infected by the Epstein Barr Virus (EBV) via the viral LMP1 gene. Tumor types which are frequently associated with EBV-infection include gastric adenocarcinoma (~10% positive), classical Hodgkin's Lymphoma (~50%), and nasopharyngeal carcinoma (~100%). Analyzing RNA expression in EBV-associated tumors, we found strong expression of CCL17, CCL22, and FOXP3, a marker of Treg, when compared to EBV-negative tumors. In fact, NPC tumors show extremely high FOXP3 levels. To further test this link, we obtained EBV-associated tumor samples and performed RNA in situ hybridization (ISH) to measure co-expression of these genes. Strong co-localization, was indeed found, further supporting a link between EBV and Treg recruitment. To directly test whether EBV-positive tumors recruit Treg into tumors via CCL22/17 upregulation, we developed models in which mice were inoculated subcutaneously with EBV-positive cancer cell lines. These EBV-positive cancer cells were assessed for chemokine production in vitro and in vivo by ELISA. We assessed tumor-infiltrating lymphocytes (TILs) in established tumors, including Treg, CD4+ and CD8+ T cells as well as T cell activation markers. Treating these tumor-bearing mice with selective and potent CCR4 small-molecule antagonists alone or in combination with checkpoint-targeting antibodies allowed us to demonstrate meaningful antitumor responses in EBV-positive tumors. Together, these data suggest that EBV-positive tumors, such as gastric adenocarcinomas, Hodgkin's lymphomas, and nasopharyngeal carcinomas, are a class of indications of particular interest and potentially increased responsiveness to small-molecule CCR4 antagonists. These results are helping to inform the ongoing FLX475 trials currently in the clinic. Citation Format: Oezcan Talay, Aparna Jorapur, Scott Jacobson, Sachie Marubayashi, Lisa Marshall, Silpa Suthram, Omar Robles, John Ketcham, Maureen K. Reilly, Ashkaan Younai, Berenger Biannic, Dennis Hu, Minna Bui, Jacob Schwarz, Paul Kassner, Gene Cutler. EBV associated tumors have increased regulatory T cell recruitment and are therefore a potential indication for treatment with potent and selective small molecule CCR4 antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4752.
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- 2018
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21. A front line police perspective of mental health issues and services
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Lisa A. Marshall and Nicola Mclean
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Male ,Mental Health Services ,Urban Population ,Decision Making ,Applied psychology ,Pathology and Forensic Medicine ,Interviews as Topic ,Nursing ,Middle Eastern Mental Health Issues & Syndromes ,Humans ,Medicine ,Mental health law ,Interpretative phenomenological analysis ,business.industry ,Social perception ,Mental Disorders ,Perspective (graphical) ,Community management ,Front line ,General Medicine ,Mental health ,Police ,Psychiatry and Mental health ,Mental Health ,Scotland ,Social Perception ,Female ,Psychology (miscellaneous) ,business ,Attitude to Health - Abstract
Background Changes in mental health service provision in most western countries have been associated with an increasing role of the police in the community management of people with mental health problems, but little is known about how the police perceive this in the UK. Objectives To investigate police officers' views on their roles in dealings with people with mental health problems and with mental health services. Methods Nine in-depth semi-structured interviews were conducted with front line police officers. These interviews were analysed for recurrent themes using interpretative phenomenological analysis. Results The recurrent themes identified were: emotional aspects of dealing with people with mental health problems and with services, impact of incidents on police resources and on people with mental health problems, success through collaborative working with health services and failure in its absence. Conclusions Police officers' experiences of work with people with mental disorder in the community in Scotland had much in common with those previously reported in the USA and in Australia. Development of more collaborative approaches and mutual respect between the police and mental health service providers would resolve many of the currently perceived difficulties. Copyright © 2010 John Wiley & Sons, Ltd.
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- 2010
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22. Barriers to effective drug addiction treatment for women involved in street-level prostitution: a qualitative investigation
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Frances M. Smith and Lisa A. Marshall
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Adult ,Mental Health Services ,medicine.medical_specialty ,Adolescent ,Population ,Poison control ,Interpersonal communication ,Suicide prevention ,Pathology and Forensic Medicine ,Risk Factors ,medicine ,Humans ,Substance Abuse, Intravenous ,Psychiatry ,education ,Sex work ,education.field_of_study ,Interpretative phenomenological analysis ,business.industry ,Human factors and ergonomics ,General Medicine ,Middle Aged ,medicine.disease ,Sex Work ,humanities ,Substance abuse ,Psychiatry and Mental health ,Ill-Housed Persons ,Patient Compliance ,Female ,Psychology (miscellaneous) ,business ,Clinical psychology - Abstract
Objectives To examine barriers to effective drug addiction treatment for women involved in street-level prostitution. Methods A qualitative approach was selected to enable a detailed exploration, in an informal and unthreatening manner, of the barriers to drug addiction treatment from the women's perspective. Nine in-depth interviews were conducted with women who were involved in street-level prostitution. Transcripts of one-to-one interviews were analysed for recurrent themes using Interpretative Phenomenological Analysis. Results Barriers to effective addiction treatment are present at psychological, interpersonal, and wider societal levels. Themes identified included: an impoverished sense of self-worth, a lack of trust and consistency in treatment, and the absence of a comprehensive treatment package. Conclusion Current services could be improved by the provision of a structured treatment programme designed to target the specific physical and psychological requirements of this population. Also, efforts to correct the fictitious, negative portrayals of women involved in prostitution are required, if treatment efficacy is to be improved. Copyright © 2007 John Wiley & Sons, Ltd.
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- 2007
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23. Protective factors for youth considered at risk of criminal behaviour: does participation in extracurricular activities help?
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Lisa A. Marshall and Jodi M. Burton
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Male ,Self-assessment ,Self-Assessment ,Adolescent ,Youth participation ,Protective factor ,Poison control ,Risk Assessment ,Suicide prevention ,Pathology and Forensic Medicine ,Developmental psychology ,Risk Factors ,Surveys and Questionnaires ,medicine ,Humans ,Cooperative Behavior ,Risk factor ,Students ,Family Characteristics ,Aggression ,Human factors and ergonomics ,General Medicine ,Psychiatry and Mental health ,Scotland ,Adolescent Behavior ,Juvenile Delinquency ,Recreation ,Female ,Crime ,Psychology (miscellaneous) ,medicine.symptom ,Psychology ,Social psychology ,Sports - Abstract
Background There is a lack of research investigating the potential protective effect of participation in extracurricular activities on youth who are at risk of engaging in delinquent activity. Aim This study examined the potential for participation in extracurricular activities to act as a protective factor for youth deemed at risk of engaging in delinquent activity. Method One hundred and sixty-nine secondary students from Glasgow, Scotland completed two questionnaires (the Youth Self-Report and an additional information sheet) requesting information about their participation in extracurricular and delinquent activities as well as their possible risk factors. Activities included sports, non-sports (hobbies and games), current activities (youth clubs and other organisations) and previous involvement in activities. Risk factors included residing in a broken home, having four or more siblings, academic failure and lacking a nonparental very important person. Delinquent activities included rule-breaking and aggressive behaviours. Results Independent samplest-tests found that females participated in significantly more non-sports and previous activities than males and that males participated in significantly more rule-breaking behaviour than females. Hierarchical multiple regression analyses found that gender and participation in sports were strong predictors of rule-breaking behaviour. A significant positive correlation was found between participation in sports and involvement in aggressive behaviour. Conclusion The results suggest that participation in extracurricular activities does not act as a protective factor for youth, regardless of whether or not they are considered to be at risk of engaging in delinquent activity. The significant correlation found between participation in sports and involvement in aggressive behaviour suggests that youth participation in sports may act as a risk factor. Copyright © 2005 Whurr Publishers Ltd.
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- 2005
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24. Abstract 4600: Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg)
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Lisa Seitz, Omar Robles, Abood Okal, Erin Riegler, Emily Karbaz, Scott Jacobson, Jenny McKinnell, Angela Wadsworth, Oezcan Talay, Paul D. Kassner, Lisa A. Marshall, David Chian, David J. Wustrow, Maureen Kay Reilly, Mikhail Zibisky, Cesar Meleza, and Jordan S. Fridman
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Cancer Research ,Chemokine ,Tumor microenvironment ,biology ,Chemokine receptor CCR5 ,business.industry ,FOXP3 ,Immune tolerance ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,Immune system ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Medicine ,CCL17 ,030212 general & internal medicine ,business - Abstract
Naturally suppressive CD4+ Foxp3+ Treg are essential for immune tolerance. Although Treg-mediated suppression of effector cells is important to control inflammation and prevent autoimmune diseases, the presence of Treg in the tumor microenvironment (TME) has been shown to dampen anti-tumor immune responses. Human Treg express CCR4, the receptor for the chemokines CCL17 and CCL22. These chemokines are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff). Preclinical and clinical data supports a role for CCR4-mediated recruitment and accumulation of Treg in the TME which can be associated with poor prognosis. Further, recent longitudinal studies in patients receiving IO agents demonstrate an influx of Treg in responding patients which may dampen optimal anti-tumor responses. Therefore, CCR4 is an ideal target to selectively block Treg recruitment into the TME. We have developed structurally unique series of small molecule antagonists of CCR4. These antagonists have cellular potencies in multiple assays (e.g. chemotaxis of primary human Treg in 100% serum) in the low double-digit nM range. Representative compounds are selective against other chemokine receptors, GPCRs and ion channels, including the hERG channel, and lack inhibition of common human CYP450 enzymes. Moreover, compounds have excellent in vitro and in vivo ADME properties, consistent with convenient oral dosing. In preclinical syngeneic tumor models, these CCR4 antagonists block Treg migration and support expansion of activated Teff. In contrast to the non-selective approach of depleting anti-CCR4 antibodies, our compounds reduce Treg in the tumor, but not in peripheral tissues such as blood, spleen or skin. In preclinical efficacy studies, CCR4 antagonists potentiate the anti-tumor effects of various checkpoint inhibitors and immune stimulators such as anti-PD-L1 and anti-CD137 antibodies. We observe enhanced tumor growth inhibition and increased tumor regressions when these agents are combined with CCR4 antagonists, without any gross toxicity. Further characterization of these CCR4 antagonists and their anti-tumor effects will be described. Citation Format: Oezcan Talay, Lisa Marshall, Cesar Meleza, Maureen K. Reilly, Omar Robles, Mikhail Zibisky, Abood Okal, Lisa Seitz, Jenny McKinnell, Scott Jacobson, Erin Riegler, Emily Karbaz, David Chian, Angela Wadsworth, Paul Kassner, David Wustrow, Jordan S. Fridman. Potent and selective C-C chemokine receptor (CCR4) antagonists potentiate anti-tumor immune responses by inhibiting regulatory T cells (Treg) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4600. doi:10.1158/1538-7445.AM2017-4600
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- 2017
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25. Screening for Colorectal Cancer: Developing a Preventive Healthcare Program Utilizing Nurse Endoscopists
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Lisa Stucky-Marshall, Nancy Eisemon, and Mark S. Talamonti
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medicine.medical_specialty ,Outpatient Clinics, Hospital ,Colorectal cancer ,Population ,Disease ,Midwestern United States ,Teaching hospital ,Nursing ,Outcome Assessment, Health Care ,medicine ,Humans ,Mass Screening ,Nurse Practitioners ,education ,Sigmoidoscopy ,Aged ,Preventive healthcare ,Marketing of Health Services ,Advanced and Specialized Nursing ,education.field_of_study ,business.industry ,Gastroenterology ,Middle Aged ,medicine.disease ,Benchmarking ,Colorectal cancer screening ,Credentialing ,Colorectal Neoplasms ,business - Abstract
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. In 2000, approximately 130,200 new cases of colorectal cancer will be diagnosed, and 56,300 persons will die from the disease (Greenlee, Murray, Boldan, & Wingo, 2000). A survey conducted for the National Colorectal Cancer Roundtable by the Gallup Organization, found that 47% of people over 50 are not being screened. The National Colorectal Cancer Awareness Month, which began in March 2000, will educate Americans age 50 and older and prescribe physicians about the importance of colorectal cancer screening tests. The effect of increased education and directing physicians to include colorectal screening for their patients will create a need for non-physician endoscopists to meet the screening needs of the population. A colorectal cancer screening center was developed at a large Midwestern teaching hospital utilizing nurse endoscopists. The purpose of this article is to provide information for institutions to develop and implement a colorectal cancer screening center utilizing nurse endoscopists.
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- 2001
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26. The Childhood Experiences of Psychopaths: A Retrospective Study of Familial and Societal Factors
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Lisa A. Marshall and David J. Cooke
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Adult ,Male ,Child abuse ,medicine.medical_specialty ,Psychopathy ,Poison control ,Social Environment ,Child Rearing ,Risk Factors ,medicine ,Humans ,Child Abuse ,Parent-Child Relations ,Child ,Psychiatry ,Retrospective Studies ,Criminal Psychology ,Family Health ,Child rearing ,Prisoners ,Antisocial personality disorder ,Social environment ,Antisocial Personality Disorder ,Middle Aged ,medicine.disease ,Criminal psychology ,Psychiatry and Mental health ,Clinical Psychology ,Personality Development ,Regression Analysis ,Societal Factors ,Factor Analysis, Statistical ,Psychology - Abstract
We compared the childhood experiences of criminal psychopaths with those of criminal nonpsychopaths, to examine whether differences in either the type or intensity of adverse experience in childhood could be identified. One hundred and five prisoners, 50 psychopaths, and 55 nonpsychopaths were assessed with the Psychopathy Checklist-Revised (PCL-R) and Childhood Experience of Care and Abuse (CECA) semistructured interviews. Both assessment measures have been demonstrated to be reliable and valid instruments. File information from both adult and child services provided corroborative material. Factor analysis of the childhood experience variables revealed two distinct factors, familial and societal, both of which were highly correlated with adult psychopathy scores. These findings suggest that the experiences psychopaths have in childhood influence adult outcome.
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- 1999
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27. New agents in gastrointestinal malignancies: Part 2: Gemcitabine in clinical practice
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Lisa Stucky-Marshall
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Oncology ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Chemotherapy ,Oncology (nursing) ,business.industry ,medicine.medical_treatment ,Oncology Nursing ,medicine.disease ,Deoxycytidine ,Gemcitabine ,Gemcitabine Hydrochloride ,Discontinuation ,Pancreatic Neoplasms ,Oncology nursing ,Quality of life (healthcare) ,Pancreatic cancer ,Internal medicine ,medicine ,Humans ,business ,medicine.drug ,Patient education - Abstract
This is part two of the two-part series on new chemotherapy agents for gastrointestinal malignancies. The first article addressed the agent irinotecan hydrochloride (CAMPTOSAR Injection, Pharmacia & Upjohn Company, Kalamazoo, MI; also investigated under the name CPT-11) for use with metastatic colon cancer. This article discusses gemcitabine hydrochloride (GEMZAR for Injection, Eli Lilly and Company, Indianapolis, IN; also referred to as dFdC) for advanced pancreatic cancer. The article reviews the current clinical use, safety profile, and key patient management guidelines for the new and novel cytotoxic agent, gemcitabine, which was approved in 1996. This agent has demonstrated activity in pancreatic cancer, is generally well tolerated, and can safely be administered on an outpatient basis. Therapy-related side effects are manageable with appropriate monitoring and intervention, and reversible with dose modification or discontinuation. As clinical and investigational use of gemcitabine increases, the oncology nurse and other members of the health care team will need to anticipate potential treatment-associated toxicities and be knowledgeable in their early identification and management. As patient advocates, oncology nurses play a key role in treatment outcome and related quality of life through expert patient education, symptom recognition, and intervention according to individual patient tolerance.
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- 1999
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28. The therapeutic potential for phospholipase A2 inhibitors
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Ruth J. Mayer and Lisa A. Marshall
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Pharmacology ,Gene isoform ,Autoimmune disease ,Leukotriene ,Cell type ,biology ,business.industry ,Prostaglandin ,Lipid signaling ,medicine.disease ,chemistry.chemical_compound ,Phospholipase A2 ,chemistry ,Enzyme inhibitor ,Immunology ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,business - Abstract
Modulation of pro-inflammatory lipid mediator production by inhibition of phospholipase A2 (PLA2) activity remains a potential target for development of new drugs for the treatment of rheumatoid arthritis or other inflammatory diseases. Evidence now exists that more than one isoform of PLA2, including types IIa and V 14 and 85 kDa PLA2, is required for production of lipid mediators. Specific isoforms may be associated with production of either the prostaglandin or leukotriene class of lipid mediators in different cell types such as monocytes and neutrophils. Characterisation of isoform-selective inhibitors in models of inflammatory disease, such as rat adjuvant arthritis or phorbol myristate acetate (PMA)-induced mouse ear oedema, suggests that both 14 kDa and 85 kDa PLA2 may contribute to the development of the disease state and that both forms of PLA2 may be targets for modulation of inflammatory disease. Much work remains to clarify fully the relative roles of different PLA2 in the aetiology of inflamm...
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- 1998
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29. Child Effects as a Source of Change in Maternal Attitudes Toward Corporal Punishment
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Robert J. Zambarano, Elizabeth E. Thompson, Lisa A. Marshall, and George W. Holden
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Intergenerational transmission ,Sociology and Political Science ,Social Psychology ,Child rearing ,Punishment (psychology) ,Communication ,media_common.quotation_subject ,050901 criminology ,05 social sciences ,medicine.disease ,Developmental psychology ,Instinct ,Developmental and Educational Psychology ,medicine ,0501 psychology and cognitive sciences ,0509 other social sciences ,Psychology ,Social psychology ,Corporal punishment ,050104 developmental & child psychology ,media_common - Abstract
It is commonly believed that parental attitudes toward child rearing are largely determined by the process of intergenerational transmission. Such a view neglects potential influences from the targets of child rearing-the children. In this study we examined bidirectional influences on mothers' attitudes toward corporal punishment by interviewing 108 mothers of 3-year-old children. Two-thirds of the mothers reported significant shifts in their attitudes since becoming mothers. The major source of that change was their children's reaction to being spanked. These data reveal how child behavior can impact parental attitudes and behavior and call for a more dynamic and multidetermined model of the determinants of child-rearing behavior.
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- 1997
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30. Tetrazole is an effective Sn-3 phosphate replacement in substrate analog inhibitors of 14 kDa phospholipase A2
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Brian Bolognese, Jerry L. Adams, Lisa A. Marshall, and Dennis Lee
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chemistry.chemical_classification ,biology ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Substrate analog ,Phosphate ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Phospholipase A2 ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Discovery ,biology.protein ,medicine ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Tetrazole ,Molecular Biology - Abstract
A series of substrate analog inhibitors of 14 kDa PLA2 possessing replacements for the sn-3 phosphate moeity was prepared and evaluated. Tetrazole 26 possessed similar in vitro inhibition potency to phosphate-containing substrate analog inhibitors, but demonstrated superior cell permeability as monitored by LTC4 release in monocytes.
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- 1997
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31. Manipulation of Distinct NFκB Proteins Alters Interleukin-1β-induced Human Rheumatoid Synovial Fibroblast Prostaglandin E2 Formation
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Kevin McGough, Eugene Mochan, Jeffrey R. Jackson, Amy K. Roshak, Lisa A. Marshall, and Marie Chabot-Fletcher
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P50 ,Consensus site ,In Vitro Techniques ,Biochemistry ,Dinoprostone ,Phospholipases A ,Arthritis, Rheumatoid ,Phospholipase A2 ,Antisense Technology ,medicine ,Humans ,Fibroblast ,Molecular Biology ,Messenger RNA ,biology ,Interleukin-8 ,Synovial Membrane ,NF-kappa B ,Transcription Factor RelA ,Membrane Proteins ,Cell Biology ,Fibroblasts ,Oligonucleotides, Antisense ,Blotting, Northern ,Molecular biology ,Up-Regulation ,Isoenzymes ,Phospholipases A2 ,medicine.anatomical_structure ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,biology.protein ,Cyclooxygenase ,Decoy ,Interleukin-1 - Abstract
Interleukin 1beta (IL-1beta) up-regulates human rheumatoid synovial fibroblast (RSF) 85-kDa phospholipase A2 (PLA2) and mitogen-inducible cyclooxygenase (COX) II. Promoter regions for these genes contain a motif that closely resembles the "classic" NFkappaB consensus site. Immunoblot analysis identified NFkappaB1 (p50), RelA (p65), and c-Rel in RSF. Upon IL-1beta-stimulation, p65 and c-Rel but not p50 protein levels were reduced suggesting nuclear translocation. IL-1beta-induced RSF nuclear extracts contained a p65-containing complex, which bound to the classical NFkappaB consensus motif. An NFkappaB classical oligonucleotide decoy produced a concentration-dependent decrease in IL-1-stimulated PGE2 production (IC50 = approximately 2 microM), indicating a role of NFkappaB. Utilization of antisense technology showed that p65 but not p50 or c-Rel mediated IL-1beta-stimulated PGE2 formation. Treated RSF could not transcribe COX II or 85-kDa PLA2 mRNA, which reduced their respective proteins. Interestingly, stimulated IL-8 production was not inhibited by the classical NFkappaB decoy but was reduced by treatment with antisense to both p65 and c-Rel supporting preferential binding of c-Rel-p65 to the "alternative" IL-8 kappaB motif. Taken together, these data provide the first direct evidence for a role of p65 in COX II and 85-kDa PLA2 gene induction and support the IL-1 activation and participation of distinct NFkappaB protein dimers in RSF prostanoid and IL-8 formation.
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- 1996
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32. High-Resolution X-ray Crystallography Reveals Precise Binding Interactions between Human Nonpancreatic Secreted Phospholipase A2 and a Highly Potent Inhibitor (FPL67047XX)
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Byung-Ha Oh, Lisa A. Marshall, Dennis Lee, Jerry L. Adams, Christopher S. Jones, Sherin S. Abdel-Meguid, Sun Shin Cha, Brian Bolognese, and Jeffrey T. Kurdyla
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Models, Molecular ,Chemical Phenomena ,Molecular model ,medicine.drug_class ,Stereochemistry ,Carboxamide ,Crystallography, X-Ray ,Phospholipases A ,Mice ,Phospholipase A2 ,Transition state analog ,Drug Discovery ,Hydrolase ,medicine ,Animals ,Humans ,Otitis ,Benzhydryl Compounds ,Enzyme Inhibitors ,gamma-Aminobutyric Acid ,chemistry.chemical_classification ,biology ,Chemistry, Physical ,Anti-Inflammatory Agents, Non-Steroidal ,Hydrogen Bonding ,Phospholipases A2 ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,X-ray crystallography ,biology.protein ,Molecular Medicine ,Crystallization - Published
- 1996
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33. Prostaglandin E2 requirement for transforming growth factor β2 inhibition of elicited macrophage 14 kDa phospholipase A2 release
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Mark McCord, Brian Bolognese, and Lisa A. Marshall
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Pharmacology ,medicine.medical_specialty ,Forskolin ,biology ,Growth factor ,medicine.medical_treatment ,Transforming growth factor beta ,chemistry.chemical_compound ,Phospholipase A2 ,Endocrinology ,Cytokine ,chemistry ,Internal medicine ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Prostaglandin E2 ,TGF beta 1 ,medicine.drug ,Transforming growth factor - Abstract
1. Cultured elicited-peritoneal macrophages release a soluble type II 14 kDa phospholipase A2 (PLA2) over time, reaching a plateau by 20-24 h of incubation and maintaining these levels over 72 h. Prostaglandin E2 (PGE2) is also produced but does not plateau until 48-72 h. 2. Transforming growth factor beta 1 (TGF beta 1) reduces cellular 14 kDa PLA2 and its subsequent release by approximately half, but does not alter PGE2 production. Co-incubation of TGF beta 1 with indomethacin interfered, in a concentration-dependent manner, with the ability of TGF beta 1 to reduce cellular 14 kDa PLA2 and its subsequent release over 24 h. The regulation of TGF beta 1 was not specific to indomethacin since other non-steroidal anti-inflammatory drugs had the same effect. This suggested that cyclooxygenase activity was essential for TGF beta 1 to exert its effect and indeed, the addition of exogenous PGE2 restored the TGF beta 1 action. 3. PGE2 alone exerted a concentration-dependent negative feedback action on elicited-macrophage 14 kDa PLA2 release. The inhibitory concentration (IC50 = approximately 180 ng PGE2 ml-1) approximated the PGE2 levels measured in the 24 h macrophage conditioned media (85-140 ng PGE2 ml-1) where PLA2 release began to plateau. Further, incubation of cells with indomethacin over 48 h resulted in the enhancement of 14 kDa PLA2 activity compared to that released from untreated cells. Forskolin failed to inhibit 14 kDa PLA2 release, suggesting PGE2 was not acting through an increase in adenylate cyclase. 4. Taken together, the data are consistent with the immunosuppressive aspects reported for both mediators during inflammation and demonstrates the requirement of PGE2 for TGF beta 1 action on the elicited macrophage.
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- 1995
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34. Investigation into the Total Phenols and Antioxidant Activity during Storage of Fruit Smoothies
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Jacob K. Agbenorhevi and Lisa J. Marshall
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Blowing a raspberry ,chemistry.chemical_compound ,Horticulture ,Antioxidant ,chemistry ,medicine.medical_treatment ,medicine ,Trolox ,Gallic acid ,Phenols - Abstract
In this study, the total phenols (TP) and antioxidant activity of three different fruit smoothies (Blackberries, Raspberry and Boysenberry (BRAB), Mango and Passion fruits (MAP) and Blackcurrant, Acerola cherries and Rosehips (BACAR)) were determined during storage by Folin-Ciocalteu and ferric reducing antioxidant power (FRAP) assays respectively. TP ranged from 1,943 to 2,692 mg L -1 gallic acid equivalent whereas FRAP from 43,217 to 126,125 µmol L -1 Trolox equivalent for the three smoothies on opening. BACAR had the highest TP and antioxidant activity. The smoothies showed significant decrease (P < 0.05) in TP during storage. The decrease in antioxidant activity was significant (P < 0.05) for BRAB and MAP only. However, the study revealed that the smoothies had high antioxidant activity even during shelf-life at 4 °C which implies that consumption of smoothies may give considerable antioxidant benefits. Correlation between TP and antioxidant activity was strong and highly significant (r = 0.890, P < 0.0001).
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- 2012
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35. An estimate of dietary exposure of acrylamide in Saudi infants
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Caroline Orfila, Melvin Holmes, Lisa J. Marshall, and M. A. Thaiban
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education.field_of_study ,Pediatrics ,medicine.medical_specialty ,Percentile ,Nutrition and Dietetics ,Dietary exposure ,Population ,Medicine (miscellaneous) ,Infant exposure ,Food group ,chemistry.chemical_compound ,Animal science ,Geography ,chemistry ,Age groups ,Acrylamide ,Toxicity ,medicine ,education - Abstract
Since its discovery in starch-rich processed foods in 2002 (1) , acrylamide, a potential carcinogen, has been widely studied both in terms of toxicity and human exposure. Using concentration data from the UK, Norway, Sweden, Switzerland and the USA, the FAO and WHO estimated the dietary intake (micrograms per kilogram bodyweight per day) for the general population to be in the range of 0.3 to 0.8 mg/kg bw/d (2) but, for children, due to lower bodyweight, the intake estimate would generally be 2 to 3 times that of adults. However, there remains a paucity of exposure estimates for other population groups including infants. In this study, 3-day 24-hour records (n = 150) from healthy Saudi infants aged 4 to 24 months (separated into age differentiated groups 4‐6, 7‐9, 10‐12, 13‐16, 17‐24 months) were used to estimate the dietary exposure of acrylamide (3) using concentration data for various food groups from published studies and in particular, we included the contribution from infant milk sources. Based upon minimum, mean and maximum acrylamide concentration levels measured in 17 foods from 34 found from the survey, the mean exposure was estimated to be 5.5 mg/kg bw/d [0.44, 6.22] with the 98 th percentile to be 24.62 [6.48, 42.06 low and high respectively] mg/kg bw/d. The WHO and FAO (2) estimated the average consumption of acrylamide in infants between 6.0 mg/kg bw/d for the 98 th percentile consumer, four times lower than the Saudi infant exposure estimate in this research. In the early age groups (4‐6 and 7‐9 months) acrylamide exposure is primarily associated with increased consumption of bottled milk and cooked vegetables, with 30.92 % and 67.46 % contribution of the total exposure. In contrast in the older groups (10‐24 months) the primary exposure is associated with rolled bread and biscuits. In addition, across all age groups there was no significant difference between the mean exposures between female and males with average 5.5 [6.1 and 5.2] mg/kg bw/d respectively. This work will be extended to include comparative estimates with the 1992 NDNS (National Dietary Nutrition Survey) UK infant study No. 3481.
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- 2012
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36. Human Keratinocytes Possess an sn-2 Acylhydrolase that is Biochemically Similar to the U937-Derived 85-kDa Phospholipase A2
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John Breton, Mark McCord, Lisa A. Marshall, and Marie Chabot-Fletcher
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Keratinocytes ,Male ,Phospholipid ,keratinocyte ,Dermatology ,Biochemistry ,Dinoprostone ,Phospholipases A ,Substrate Specificity ,chemistry.chemical_compound ,Cytosol ,Phospholipase A2 ,indomethacin ,Microsomes ,Phosphatidylcholine ,arachidonic acid ,Tumor Cells, Cultured ,medicine ,Humans ,Molecular Biology ,Calcimycin ,Cells, Cultured ,Phosphatidylethanolamine ,prostaglandin E2 ,biology ,Infant, Newborn ,Antibodies, Monoclonal ,Cell Biology ,scalaradial ,inhibitor ,Molecular Weight ,Phospholipases A2 ,medicine.anatomical_structure ,chemistry ,biology.protein ,Microsome ,phospholipase A2 ,Arachidonic acid ,lipids (amino acids, peptides, and proteins) ,Keratinocyte - Abstract
The phospholipase A2 (PLA2) activities that are localized in the keratinocyte cytosolic and microsomal fractions were biochemically and pharmacologically characterized. The cytosol and to a lesser extent the microsome were sensitive to heat treatment and stable in the presence of sulfhydryl reducing agents. Both fractions were almost totally inactivated by reduction of pH to 2. The cytosolic activity demonstrated a sevenfold preference for arachidonic acid over oleic acid in the sn-2 position of substrate phospholipid and the microsome exhibited a fourfold preference. Neither the cytosol nor the microsome was inactivated by a neutralizing mouse monoclonal antibody 3F10 generated against recombinant human (rh) type II 14-kDa PLA2. Western immunoblot analysis of both fractions identified a high – molecular-mass protein in keratinocyte cytosol but not the microsome that migrated with rh 85-kDa PLA2. Neither the sytosol nor the microsome possessed immunoreactive bands that migrated with rh type II 14-kDa PLA2 when probed with monoclonal antibody 3F10. Further analysis of the cytosolic activity showed that it was activated by submicromolar concentrations of Ca2+ reduced by arachidonyl trifloromethylketone, a selective 85-kDa PLA2 inhibitor, but was unaffected by C-7 phosphonate phospholipid, a selective 14-kDa PLA2 transition state inhibitor. Taken together, the data supports the existence of a PLA2 activity in the cytosol that displays characteristics that are indistinguishable from those exhibited by the 85-kDa PLA2. Alternatively, both the cytosol and microsome were devoid of type II 14-kDa – like PLA2 activity. The failure of 12-epi scalaradial, a 14-kDa PLA 2 inhibitor, to modify A23187-stimulated keratinocyte prostaglandin E2 release, was consistent with the biochemistry and suggests that the 85-kDa PLA2 may play an important role in keratinocyte prostaglandin E2 formation.
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- 1994
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37. Flavanols and methylxanthines in commercially available dark chocolate: a study of the correlation with nonfat cocoa solids
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Swen Langer, Andrea J. Day, Michael R. A. Morgan, and Lisa J. Marshall
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Flavonoids ,Cacao ,Plant Extracts ,Polyphenols ,Catechin ,General Chemistry ,Health benefits ,Dark chocolate ,food.food ,chemistry.chemical_compound ,food ,chemistry ,Proanthocyanidin ,Polyphenol ,Fruits and vegetables ,Xanthines ,medicine ,Food science ,General Agricultural and Biological Sciences ,Caffeine ,Theobromine ,medicine.drug - Abstract
Intake of flavanols, a subgroup of dietary polyphenols present in many fruits and vegetables, may be associated with health benefits, particularly with reducing the risk of coronary diseases. Cocoa and chocolate products are rich in flavanol monomers, oligomers, and polymers (procyanidins). This study used normal phase HPLC to detect, identify, and quantify epicatechin, catechin, total monomers, procyanidin oligomers and polymers in 14 commercially available chocolate bars. In addition, methylxanthines (theobromine and caffeine) were also quantified. Nonfat cocoa solids (NFCS) were determined both gravimetrically and by calculation from theobromine contents. The flavanol levels of 12 commonly consumed brands of dark chocolate have been quantified and correlated with % theobromine and % NFCS. Epicatechin comprised the largest fraction of total chocolate flavonoids, with the remainder being catechin and procyanidins. Calculated NFCS did not reflect epicatechin (R(2) = 0.41) or total flavanol contents (R(2) = 0.49). Epicatechin (R(2) = 0.96) was a reliable marker of total flavanols, catechin (R(2) = 0.67) to a lesser extent. All dark chocolate tested contained higher levels of total flavanols (93.5-651.1 mg of epicatechin equiv/100 g of product) than a milk or a white "chocolate" (40.6 and 0.0 mg of epicatechin equiv/100 g, respectively). The amount and integrity of procyanidins often suffer in the manufacturing of chocolate, chiefly due to oxidation and alkalinization. In this study, the labeled cocoa content of the chocolate did not always reflect analyzed levels of flavonoids. Increasingly, high % NFCS is being used commercially to reflect chocolate quality. If the flavanol content of chocolate is accepted to be a key determinant of health benefits, then continued monitoring of flavanol levels in commercially available chocolate products may be essential for consumer assurance.
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- 2011
38. Coexistence of two biochemically distinct phospholipase A2 activities in human platelet, monocyte, and neutrophil
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Amy K. Roshak and Lisa A. Marshall
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Blood Platelets ,Male ,Carboxylic Ester Hydrolases ,Neutrophils ,Neutrophile ,Human platelet ,Biology ,Biochemistry ,Monocytes ,Phospholipases A ,Substrate Specificity ,Cytosol ,Phospholipase A2 ,Microsomes ,Synovial Fluid ,medicine ,Humans ,Platelet ,Molecular Biology ,chemistry.chemical_classification ,Arachidonic Acid ,Monocyte ,Cell Biology ,Hydrogen-Ion Concentration ,Isoenzymes ,Molecular Weight ,Dithiothreitol ,Phospholipases A2 ,medicine.anatomical_structure ,Enzyme ,chemistry ,biology.protein - Abstract
The cell-associated phospholipase A2 (PLA2) activities of the human platelet, neutrophil, and monocyte were simultaneously characterized, utilizing the biochemical differences observed between the 14 kDa (kilodalton), type II PLA2 isolated from inflammatory human synovial joint fluid (HSF) and the arachidonic acid (AA) specific, 85-kDa high molecular mass (HMM) PLA2 isolated from the cytosol of a U937 monocytic cell line. The HSF PLA2 can be distinguished from the HMM PLA2 by its resistance to acid treatment, sensitivity to a sulfhydryl reducing agent, lack of preference for the fatty acid on the sn-2 position of phospholipid substrate, and inhibition by the C-7 phosphonate–phospholipid transition-state PLA2 inhibitor. Evaluation of all three cell types revealed that HMM-like PLA2 activity was found predominantly in the cytosolic fractions, although detection in neutrophil cytosol required more concentrated preparations and the use of high specific activity [3H]AA-labeled Escherichia coli. HSF-PLA2-like activity was measured in microsomal and cytosolic fractions of all three cell types, but was found in neutrophil cytosol only after treatment with acid. Further HMM-PLA2-specific interfering agents in neutrophil cytosol were observed and exemplifies one problem in assigning the existence of this enzyme in crude broken cell preparations using activity measurements alone. The role that these two enzymes play in eicosanoid production of the respective cell types remains to be studied.Key words: phospholipase A2, arachidonic acid, neutrophil, platelet, monocyte, cytosol, microsome.
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- 1993
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39. The molecular basis for T cell help in humoral immunity: CD40 and its ligand, gp39
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Lisa S. Marshall, Alejandro Aruffo, Randolph J. Noelle, and Jeffrey A. Ledbetter
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Antigens, Differentiation, T-Lymphocyte ,Cell type ,T-Lymphocytes ,T cell ,CD40 Ligand ,Immunology ,Biology ,Ligands ,Lymphocyte Activation ,Immune system ,Cell–cell interaction ,Antigens, CD ,medicine ,Animals ,Humans ,Immunology and Allergy ,CD40 Antigens ,Molecular Biology ,Autoimmune disease ,B-Lymphocytes ,Membrane Glycoproteins ,CD40 ,Immunologic Deficiency Syndromes ,T-Lymphocytes, Helper-Inducer ,medicine.disease ,Acquired immune system ,Antigens, Differentiation, B-Lymphocyte ,medicine.anatomical_structure ,Antibody Formation ,Mutation ,Humoral immunity ,biology.protein - Abstract
The identification of the gp39-CD40 as an essential ligand-receptor pair for TD humoral immunity offers new insights into the regulation of TD immune responses. It is apparent that alterations in the regulation of gp39 expression, either by mutations in the gp39 gene (HIM patients) or by other factors that influence expression (like cyclosporine), have an overwhelming effect on humoral immunity. Whether other arms of the immune response are targets of gp39 action is unknown at this time. However, the identification of CD40 as the receptor for gp39 provides clues as to other CD40-expressing cell types (folicular dendritic cells, thymic epithelial cells, etc.) that might be regulated by activated CD4+ T cells. The immunosuppressive effects of anti-gp39 on primary and secondary humoral immunity, as well as the beneficial therapeutic effects of anti-gp39 on the progression of autoimmune disease in animal models, suggest that this ligand-receptor pair is an ideal target for the therapeutic intervention.
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- 1993
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40. Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways
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Holger Wesche, Rashmi Gupta, Patricia E. Burger, Xiangyun Wang, Roy Blum, Christopher S. Ontiveros, Gene Cutler, Sarah N. Salm, E. Lynette Wilson, Alexander Kamb, David Moscatelli, Xiaozhong Xiong, Lisa A. Marshall, Jiri Zavadil, Division of Immunology, and Faculty of Health Sciences
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Male ,Mesenchyme ,Cell Biology/Developmental Molecular Mechanisms ,lcsh:Medicine ,Stem cell factor ,Stem cells ,Cell Communication ,Biology ,Mesoderm ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cancer stem cell ,Prostate gland ,medicine ,Animals ,Stem Cell Niche ,lcsh:Science ,030304 developmental biology ,0303 health sciences ,Prostate cancer ,Multidisciplinary ,lcsh:R ,Mesenchymal stem cell ,Urology/Prostate Cancer ,Prostate ,Epithelial Cells ,Embryonic stem cell ,Gene regulation ,Cell biology ,Developmental Biology/Stem Cells ,Endothelial stem cell ,Mice, Inbred C57BL ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,lcsh:Q ,Gene expression ,Epidermis ,Stem cell ,Adult stem cell ,Signal Transduction ,Research Article - Abstract
Background Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system. Methodology/Principal Findings We isolated fetal murine urogenital sinus epithelium and urogenital sinus mesenchyme and determined their differentially expressed genes. To distinguish transcripts that are shared by other developing epithelial/mesenchymal compartments from those that pertain to the prostate stem cell niche, we also determined the global gene expression of epidermis and dermis of the same embryos. Our analysis indicates that several of the key transcriptional components that are predicted to be active in the embryonic prostate stem cell niche regulate processes such as self-renewal (e.g., E2f and Ap2), lipid metabolism (e.g., Srebp1) and cell migration (e.g., Areb6 and Rreb1). Several of the enriched promoter binding motifs are shared between the prostate epithelial/mesenchymal compartments and their epidermis/dermis counterparts, indicating their likely relevance in epithelial/mesenchymal signaling in primitive cellular compartments. Based on differential gene expression we also defined ligand-receptor interactions that may be part of the molecular interplay of the embryonic prostate stem cell niche. Conclusions/Significance We provide a comprehensive description of the transcriptional program of the major regulators that are likely to control the cellular interactions in the embryonic prostatic stem cell niche, many of which may be common to mammalian niches in general. This study provides a comprehensive source for further studies of mesenchymal/epithelial interactions in the prostate stem cell niche. The elucidation of pathways in the normal primitive niche may provide greater insight into mechanisms subverted during abnormal proliferative and oncogenic processes. Understanding these events may result in the development of specific targeted therapies for prostatic diseases such as benign prostatic hypertrophy and carcinomas.
- Published
- 2010
41. A Novel Wide Field-of-View Imaging System for Real-Time, Intra-Operative Tumor Bed Assessment
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Yongbaek Kim, Linda G. Griffith, W. David Lee, Jeffrey K. Mito, Jorge Ferrer, David G. Kirsch, Brian E. Brigman, David Dankort, Moungi G. Bawendi, Lisa F. Marshall, Rebecca D. Dodd, William C. Eward, Martin McMahon, and Chang-Lung Lee
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Intra operative ,business.industry ,medicine.disease ,Wide field ,Tumor margin ,Margin (machine learning) ,White light ,Medicine ,Tumor bed ,Sarcoma ,business ,Nuclear medicine ,Preclinical imaging ,Biomedical engineering - Abstract
A fluorescence-based imaging system has been developed for real-time, in vivo tumor margin assessment with microscopic sensitivity. Intra-operative imaging results have matched post-surgical histo-pahtological margin assessment in all the sarcoma mice cases tested so far.
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- 2010
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42. Molecular Signatures of Prostate Stem Cells Reveal Novel Signaling Pathways and Provide Insights into Prostate Cancer
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David Moscatelli, Roy Blum, Christopher S. Ontiveros, Rashmi Gupta, Lisa A. Marshall, Xiaozhong Xiong, Jiri Zavadil, E. Lynette Wilson, Holger Wesche, Gene Cutler, Patricia E. Burger, Alexander Kamb, Sarah N. Salm, Xiangyun Wang, Division of Immunology, and Faculty of Health Sciences
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Male ,Cellular differentiation ,lcsh:Medicine ,Prostate cancer ,Mice ,0302 clinical medicine ,Prostate ,Transforming Growth Factor beta ,Prostate gland ,lcsh:Science ,Promoter Regions, Genetic ,Genetics ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,Stem Cells ,Urology/Prostate Cancer ,Developmental Biology/Stem Cells ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Multigene Family ,Stem cell ,Adult stem cell ,Research Article ,Protein Binding ,Signal Transduction ,Adult ,Biology ,Models, Biological ,03 medical and health sciences ,Fetus ,Cancer stem cell ,medicine ,Adults ,Animals ,Humans ,RNA, Messenger ,030304 developmental biology ,Cell Proliferation ,Gene Expression Profiling ,lcsh:R ,Prostatic Neoplasms ,Cell Biology ,medicine.disease ,Gene regulation ,Gene expression profiling ,Mice, Inbred C57BL ,Lipid metabolism ,TGF-beta signaling cascade ,Receptors, Aryl Hydrocarbon ,Cancer research ,lcsh:Q ,Gene expression ,Transcription Factors - Abstract
BACKGROUND:The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS:A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-beta has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. CONCLUSIONS/SIGNIFICANCE:Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors.
- Published
- 2009
43. Abstract 4290: Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
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Jan Melom, Mikhail Zibinsky, Nick Shah, Hunter P. Shunatona, Maureen Kay Reilly, Jenny McKinnell, Jordan S. Fridman, Jay P. Powers, Pia Bjork, Juan C. Jaen, Hilary Plake Beck, James Ross Walker, Maksim Osipov, Adam Park, Matthew J. Walters, Rajkumar Noubade, David Chian, Stephen W. Young, and Lisa A. Marshall
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Cancer Research ,Tumor microenvironment ,biology ,business.industry ,Melanoma ,T cell ,Cancer ,Ipilimumab ,medicine.disease ,biology.organism_classification ,HeLa ,medicine.anatomical_structure ,Oncology ,Immunology ,medicine ,biology.protein ,Cancer research ,Antibody ,Indoleamine 2,3-dioxygenase ,business ,medicine.drug - Abstract
The IDO1 pathway has been proposed to mediate immunosuppressive effects in the tumor microenvironment through its role in the catabolism of tryptophan, resulting in effects on the differentiation and proliferation of T cells. IDO1 inhibition has shown promising clinical benefit as well as exacerbated toxicity in the treatment of melanoma, when combined with the anti-CTLA-4 antibody ipilimumab. We have discovered a novel class of highly selective small molecule inhibitors of IDO1 which surpass the potency of the compounds currently in clinical development. These compounds potently inhibit IDO1 activity in IFN-γ stimulated HeLa cells with single digit nM potency. Importantly, they also retain their potency in the presence of human serum, with IC50 values ranging between 5 and 15 nM in this more physiologically relevant media. Consistent with the role of IDO1+ dendritic cells in the suppression of T cell proliferation, this series of molecules is capable of restoring the proliferative capacity of human T cells (which is inhibited by allogeneic IDO1+ dendritic cells) with EC50 values of 2-3 nM. The molecules exhibit preclinical PK characteristics that are suitable for assessing the contribution of IDO1 to tumor growth in murine models, both alone and in combination with other therapeutic agents. The compounds have high metabolic stability against cultured human hepatocytes and exhibit preclinical PK and ADME characteristics consistent with once-daily dosing in humans. The full preclinical profile of one of these molecules, selected for clinical evaluation, will be the focus of this presentation. In conclusion, we have discovered a novel class of small molecule inhibitors of IDO1, which provides a preclinical basis for the clinical evaluation of a next generation IDO1 inhibitor in combination with other therapeutic agents. Citation Format: Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen. Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4290. doi:10.1158/1538-7445.AM2015-4290
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- 2015
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44. Increased lysosomal uptake of methotrexate-polyglutamates in two methotrexate-resistant cell lines with distinct mechanisms of resistance
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Lisa A. Marshall, Erasmus Schneider, Myung S. Rhee, Alexey Khodjakov, and Lars Hofmann
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musculoskeletal diseases ,Osmosis ,Cell ,Biology ,Biochemistry ,immune system diseases ,Lysosome ,Cell Line, Tumor ,medicine ,Humans ,heterocyclic compounds ,skin and connective tissue diseases ,Pharmacology ,Polyglutamate ,Hydrolysis ,Biological Transport ,Molecular biology ,In vitro ,beta-N-Acetylhexosaminidases ,Cytosol ,medicine.anatomical_structure ,Methotrexate ,Mechanism of action ,Microscopy, Fluorescence ,Polyglutamic Acid ,Cell culture ,Drug Resistance, Neoplasm ,Efflux ,medicine.symptom ,Lysosomes - Abstract
Methotrexate (MTX) resistance in mitoxantrone-selected MCF7/MX cells and in MTX-selected CEM/MTX cells is associated with reduced drug accumulation, albeit caused by different mechanisms. In addition, in both resistant cell lines the proportion of active long-chain MTX-polyglutamate (MTX-PG) metabolites is reduced relative to that in the respective parental cell line. Previous studies by others have implied that increased lysosomal uptake could affect the rate of MTX-PG hydrolysis, and hence the length distribution of the polyglutamate chains. However, in the two cell line pairs studied, the number of lysosomes per cell was not different between the corresponding parental and resistant cells. Instead, we observed a two- to three-fold increased facilitative uptake of MTX-Glu 4 by the lysosomes from these two independently derived MTX-resistant cell lines, compared to uptake by lysosomes from their corresponding parental cells. Enhanced lysosomal uptake of MTX-Glu 4 was reflected in an increased maximal uptake velocity, without a change in the apparent substrate affinity. In addition, the rate of MTX efflux from lysosomes from CEM/MTX cells was two-fold faster than from lysosomes from CEM cells. Consistent with this observation, the relative amount of short-chain MTX-Glu 1+2 species, as a fraction of the total amount of all MTX-Glu 1−4 species combined, was only half as large in lysosomes from CEM/MTX cells as in lysosomes from CEM cells. Together, these results suggest the possibility that increased lysosomal uptake, and hence enhanced sequestration of MTX-PGs in resistant cells, contributes to the development of high-level MTX resistance by decreasing the cytosolic levels of MTX-PGs.
- Published
- 2005
45. A potent and selective nonpeptide antagonist of CXCR2 inhibits acute and chronic models of arthritis in the rabbit
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Henry M. Sarau, Osamu Kajikawa, Qi Jin, Widdowson Katherine L, James J. Foley, Patricia L. Podolin, Judithann M. Lee, Peter T. Buckley, John R. White, Tonja R. Hagen, Lisa A. Marshall, Richard B. Goodman, Dulcie B. Schmidt, Douglas W. P. Hay, and Brian Bolognese
- Subjects
Lipopolysaccharides ,Leukocyte migration ,Neutrophils ,Ovalbumin ,Immunology ,Arthritis ,Pharmacology ,In Vitro Techniques ,Receptors, Interleukin-8B ,Proinflammatory cytokine ,Arthritis, Rheumatoid ,Immunology and Allergy ,Medicine ,Synovial fluid ,Animals ,Humans ,Urea ,Receptor ,Leukotriene ,business.industry ,Anti-Inflammatory Agents, Non-Steroidal ,Interleukin-8 ,Antagonist ,Chemotaxis ,medicine.disease ,Arthritis, Experimental ,Recombinant Proteins ,Chemotaxis, Leukocyte ,Acute Disease ,Chronic Disease ,Female ,Rabbits ,business - Abstract
Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits 125I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC50 = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC50 = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-α, IL-8, PGE2, leukotriene B4, and leukotriene C4 levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-α and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC50 = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.
- Published
- 2002
46. Scytonemin--a marine natural product inhibitor of kinases key in hyperproliferative inflammatory diseases
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Lisa A. Marshall, Brian L. Marquez, Amy K. Roshak, Elizabeth A. Capper, Christopher S. Stevenson, William H. Gerwick, Robert S. Jacobs, and Krista J. S. Grace
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Male ,Umbilical Veins ,Indoles ,Immunology ,Pharmacology toxicology ,Inflammation ,Cell Cycle Proteins ,Scytonemin ,Biology ,Protein Serine-Threonine Kinases ,Cyanobacteria ,chemistry.chemical_compound ,Mice ,Phenols ,Proto-Oncogene Proteins ,Protein Kinase C beta ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Protein Kinase Inhibitors ,Protein Kinase C ,Pharmacology ,Natural product ,Protein-Serine-Threonine Kinases ,Kinase ,Pigments, Biological ,Recombinant Proteins ,Isoenzymes ,Biochemistry ,chemistry ,Endothelium, Vascular ,medicine.symptom ,Protein Kinases ,Cell Division - Published
- 2002
47. Abstract 3648: Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics
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Cariad Chester, Idit Sagiv-Barfi, Steve Young, Jay P. Powers, Lisa A. Marshall, Juan C. Jaen, Amanda Rajapaksa, Erin Waller, Holbrook E Kohrt, Jonathan Hebb, and Rajkumar Noubade
- Subjects
chemistry.chemical_classification ,Cancer Research ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Melanoma ,Cancer ,Immunosuppression ,medicine.disease ,medicine.anatomical_structure ,Enzyme ,Oncology ,Western blot ,chemistry ,Immunology ,medicine ,Cancer research ,Lymph ,Signal transduction ,business ,Lymph node - Abstract
Objective: Inhibition of indoleamine-2,3-dioxygenase-1 (IDO-1), indoleamine-2,3- dioxygenase-2 (IDO-2), and/or tryptophan-2,3-dioxygenase (TDO) represent novel opportunities for reversing the immunosuppressed microenvironment found in cancer patients. However, little is known about the relative expression of these enzymes in tumors and associated lymph nodes of mouse tumor models, including those previously utilized in the preclinical characterization of tool compounds or even clinical candidates that inhibit one of these enzymes. This report describes the systematic characterization of expression of these enzymes in several of the most commonly used mouse tumor models. Study Design: Tumor models evaluated included B16F10 melanoma, B16-GMCSF melanoma and PAN02 pancreatic in C57BL/6 mice, and 4T1 breast and CT26 colon in Balb/c mice. Cells were injected s.c. into the flanks of 8-week old female mice. In each model, tumors and draining lymph nodes were collected from separate cohorts of mice when the mean tumor volumes reached 100 and 1,000 mm3, respectively. Expression of the 3 enzymes of interest was assessed using a variety of techniques, including qRT-PCR, Western blot and FACS. Results: A highly complex picture arises from our study. Expression levels of each of the enzymes studied here were highly dependent on the choice of tumor cell, the tissue analyzed (tumor vs. lymph node), as well as the stage of growth of the tumor. In general, the most commonly expressed of the 3 enzymes was IDO-1, primarily on tumor cells and dendritic cells in the lymph nodes. Conclusion: It is critically important, in the preclinical evaluation of potential new drugs, to select mouse models that recapitulate specific and well-characterized elements of the signaling pathway targeted by those drugs. The results presented in this communication should be of particular interest to those investigators pursuing a therapeutic strategy of immunosuppression reversal. Citation Format: Rajkumar Noubade, Holbrook Kohrt, Lisa Marshall, Idit Sagiv-Barfi, Jonathan Hebb, Cariad Chester, Amanda Rajapaksa, Erin Waller, Steve Young, Jay Powers, Juan Jaen. Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3648. doi:10.1158/1538-7445.AM2014-3648
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- 2014
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48. New agents in gastrointestinal malignancies: Part 1: Irinotecan in clinical practice
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Lisa Stucky-Marshall
- Subjects
Oncology ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,Irinotecan ,Pancreatic cancer ,Internal medicine ,medicine ,Irinotecan Hydrochloride ,Humans ,Neoplasm Metastasis ,Chemotherapy ,Oncology (nursing) ,business.industry ,Oncology Nursing ,Cancer ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Gemcitabine ,Discontinuation ,Pancreatic Neoplasms ,Camptothecin ,business ,Colorectal Neoplasms ,medicine.drug - Abstract
In 1996 two chemotherapy agents were introduced by the U.S. Food and Drug Administration (FDA) with indications for the gastrointestinal malignancies for advanced colon and pancreatic cancers. The agents approved were irinotecan hydrochloride (CAMPTOSAR Injection, Pharmacia & Upjohn Company, Kalamazoo, MI; also investigated under the name CPT-11) for the second-line treatment of metastatic colorectal cancer, recurrent or relapsed, after 5-fluorouracil (5-FU)-based therapy, and gemcitabine hydrochloride (GEMZAR for injection, Eli Lilly and Company, Indianapolis, IN; also referred to as dFdC) for first-line treatment of locally advanced and metastatic cancer of the pancreas. Irinotecan and gemcitabine, with demonstrated activity in colorectal and pancreatic cancer, respectively, are generally well tolerated and can be administered safely on an outpatient basis. Clinically relevant activity is documented for both single agents. Therapy-related side effects are manageable with appropriate monitoring and intervention, and reversible with dose modification or discontinuation. This article is one of a two-part series on new chemotherapeutic agents for gastrointestinal malignancies. The first in the series, this article addresses the agent irinotecan hydrochloride (CAMPTOSAR Injection). The second article, appearing in a subsequent issue, will review gemcitabine hydrochloride (Gemzar for Injection). Both articles review the current clinical use, safety profile, and key patient management guidelines for these new and novel cytotoxics. As clinical and investigational use of irinotecan and gemcitabine increases, the oncology nurse and other members of the health care team will need to anticipate potential treatment associated toxicities and be knowledgeable in their early identification and management. As patient advocates, oncology nurses play a key role in treatment outcome and related quality of life through expert patient education, symptom recognition, and intervention individualized to patient tolerance. This first article of the series addresses irinotecan, which in 1996 was approved for the second-line therapy of metastatic colorectal cancer, recurrent or elapsed, after 5-fluorouracil (5-FU).
- Published
- 1999
49. In Vivo Models of Inflammation
- Author
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Lisa A. Marshall, Douglas W. Morgan, and Christopher S. Stevenson
- Subjects
Human disease ,Animal model ,business.industry ,Inflammatory response ,Medicine ,Gene transfer ,business ,Data science ,Biomedical engineering ,Pharmaceutical industry - Abstract
Purpose of In vivo Models of Inflammation is to provide the biomedical researcher in both the pharmaceutical industry and academia with a description of the state of the art animal model systems used to emulate diseases with components of inflammation. The aim of this second edition is to act as a complement to the first by describing and updating the standard models that are most utilized for specific disease areas. In addition, this 2nd edition includes new models exploring emerging areas of inflammation research. It provides detailed descriptions of the methodologies and uses of the most significant models. This includes current information regarding agents that demonstrate efficacy, those that do not and those that can be used as standard controls. The focus remains on those models that serve as pre-clinical correlates to human disease as well as those that represent components of the inflammatory response. New approaches to the development of future models in selected therapeutic areas have been highlighted. The focus on novel technologies that are vital for innovative in vivo research has also been expanded to include chapters on the use of transgenic and gene transfer technologies, nanotechnology, and stem cells. The book provides the scientist with an up-to-date reference manual for selecting the best animal model for their specific question. Chapters describing current regulations in the United States, United Kingdom, and Japan are also included.
- Published
- 1999
- Full Text
- View/download PDF
50. Beta-lactams SB 212047 and SB 216754 are irreversible, time-dependent inhibitors of coenzyme A-independent transacylase
- Author
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Don E. Griswold, William E. Bondinell, Marie Chabot-Flecher, Floyd H. Chilton, Lisa A. Marshall, Ruth J. Mayer, James D. Winkler, and Chiu-Mei Sung
- Subjects
Lactams ,Neutrophils ,Coenzyme A ,Anti-Inflammatory Agents ,Inflammation ,beta-Lactams ,Cell Line ,chemistry.chemical_compound ,Mice ,In vivo ,Acetyltransferases ,Microsomes ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,Platelet Activating Factor ,IC50 ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Platelet-activating factor ,Lipid signaling ,Enzyme ,chemistry ,Biochemistry ,Phorbol ,Molecular Medicine ,Eicosanoids ,medicine.symptom ,Acyl-Carrier Protein S-Acetyltransferase - Abstract
The enzyme coenzyme A-independent transacylase (CoA-IT) has been demonstrated to be the key mediator of arachidonate remodeling, a process that moves arachidonate into 1-ether-containing phospholipids. Blockade of CoA-IT by reversible inhibitors has been shown to block the release of arachidonate in stimulated neutrophils and inhibit the production of eicosanoids and platelet-activating factor. We describe novel inhibitors of CoA-IT activity that contain a beta-lactam nucleus. beta-Lactams were investigated as potential mechanism-based inhibitors of CoA-IT on the basis of the expected formation of an acyl-enzyme intermediate complex. Two beta-lactams, SB 212047 and SB 216754, were shown to be specific, time-dependent inhibitors of CoA-IT activity (IC50 = 6 and 20 microM, respectively, with a 10-min pretreatment time). Extensive washing and dilution could not remove the inhibition, suggesting it was irreversible. In stimulated human monocytes, SB 216754 decreased the production of eicosanoids in a time-dependent manner. In an in vivo model of phorbol ester-induced ear inflammation, SB 216754 was able to inhibit indices of both edema and cell infiltration. Taken together, the results support two hypotheses: 1) CoA-IT activity is important for the production of inflammatory lipid mediators in stimulated cells and in vivo and 2) the mechanism by which CoA-IT acts to transfer arachidonate is through an acyl-enzyme intermediate.
- Published
- 1998
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