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1.
Occup Med (Lond) ; 73(9): 541-546, 2023 12 30.
Article in English | MEDLINE | ID: mdl-38072465

ABSTRACT

BACKGROUND: Workplace violence (WPV) is a growing issue in health care with far-reaching consequences for health workers' physical and psychological well-being. While some medical specialities like emergency medicine have always been considered at higher risk for WPV, several studies have also reported its occurrence in radiology. AIMS: This systematic review aimed to comprehensively synthesize the types of WPV in radiology, its psychological impact, and the underlying risk and protective factors. METHODS: We searched five electronic databases (PubMed, Web of Science Core Collection, Scopus, PsycINFO and CINAHL) and additional literature, including grey literature, and established weekly search alerts. Two reviewers independently conducted all methodological steps, involving a third reviewer in case of disagreement. RESULTS: Of the 12 205 retrieved records, 103 full-text articles were evaluated, and 15 studies were included. Across studies, verbal aggression, sexual harassment (mostly against women) and physical violence were experienced by up to 100%, 85% and 46% of health workers, respectively. Perpetrators were patients and patients' caregivers, followed by co-workers. Victims suffered from various psychological symptoms, such as anxiety (22%-54%), fear (6%-39%), depression (32%) and repeated disturbing memories (21%). Risk factors included female gender, understaffing, worker inexperience, poor communication and lengthy waiting times. Social support and security personnel presence were among the identified protective factors. CONCLUSIONS: Health workers are at high risk of experiencing WPV in the radiological setting, with a strong psychological impact. Radiological departments should create a safe healthcare environment that actively manages the identified risk factors and offers psychological support to affected workers.


Subject(s)
Radiology , Workplace Violence , Humans , Female , Workplace Violence/psychology , Health Personnel/psychology , Aggression , Health Facilities , Workplace/psychology
2.
BMC Health Serv Res ; 20(1): 850, 2020 Sep 10.
Article in English | MEDLINE | ID: mdl-32912259

ABSTRACT

BACKGROUND: Clinical practice guidelines (CPGs) include evidence-based recommendations for managing obesity in adolescents. However, information on how health care providers (HCPs) implement these recommendations in day-to-day practice is limited. Our objectives were to explore how HCPs deliver weight management health services to adolescents with obesity and describe the extent to which their reported practices align with recent CPGs for managing pediatric obesity. METHODS: From July 2017 to January 2018, we conducted a qualitative study that used purposeful sampling to recruit HCPs with experience in adolescent weight management from multidisciplinary, pediatric weight management clinics in Edmonton and Ottawa, Canada. Data were collected using audio-recorded focus groups (4-6 participants/group; 60-90 min in length). We applied inductive, semantic thematic analysis and the congruent methodological approach to analyze our data, which included transcripts, field notes, and memos. Qualitative data were compared to recent CPGs for pediatric obesity that were published by the Endocrine Society in 2017. Of the 12 obesity 'treatment-related' recommendations, four were directly relevant to the current study. RESULTS: Data were collected through three focus groups with 16 HCPs (n = 10 Edmonton; n = 6 Ottawa; 94% female; 100% Caucasian), including dietitians, exercise specialists, nurses, pediatricians, psychologists, and social workers. We identified three main themes that we later compared with CPG recommendations, including: (i) discuss realistic expectations regarding weight management (e.g., shift focus from weight to health; explore family cohesiveness; foster delayed vs instant gratification), (ii) personalize weight management (e.g., address personal barriers to change; consider developmental readiness), and (iii) exhibit non-biased attitudes and practices (e.g., de-emphasize individual causes of obesity; avoid making assumptions about lifestyle behaviors based on weight). Based on these qualitative findings, HCPs applied all four CPG recommendations in their practices. CONCLUSIONS: HCPs provided practical insights into what and how they delivered weight management for adolescents, which included operationalizing relevant CPG recommendations in their practices.


Subject(s)
Delivery of Health Care/methods , Health Personnel , Pediatric Obesity/therapy , Adolescent , Adult , Canada , Child , Exercise , Family , Female , Focus Groups , Humans , Male , Middle Aged , Pediatric Obesity/prevention & control , Pediatric Obesity/psychology , Practice Guidelines as Topic , Precision Medicine
3.
BMC Pediatr ; 19(1): 418, 2019 11 08.
Article in English | MEDLINE | ID: mdl-31699060

ABSTRACT

BACKGROUND: Lifestyle modifications represent the first line of treatment in obesity management; however, many adolescents with obesity do not meet lifestyle recommendations. Given that adolescents are rarely consulted during health policy development and in the design of lifestyle interventions, their first-hand experiences, preferences, and priorities may not be represented. Accordingly, our purpose was to explore adolescents' lifestyle treatment recommendations to inform policy and program decisions. METHODS: Conducted from July 2017 to January 2018, this study adhered to a qualitative, crosslanguage, patient-oriented design. We recruited 19 13-17-year-old adolescents (body mass index [BMI] ≥85th percentile) seeking multidisciplinary treatment for obesity in geographically and culturally diverse regions of Canada. Adolescents participated in one-on-one, in-person, semi-structured interviews in English or French. Interviews were audio-recorded, transcribed verbatim, managed using NVivo 11, and analyzed using quantitative and qualitative content analysis by two independent researchers. RESULTS: Adolescents' recommendations were organized into five categories, each of which denotes health as a collective responsibility: (i) establish parental support within limits, (ii) improve accessibility and availability of 'healthy foods', (iii) limit deceptive practices in food marketing, (iv) improve accessibility and availability of varied physical activity opportunities, and (v) delay school start times. Respect for individual autonomy and decision-making capacity were identified as particularly important, however these were confronted with adolescents' partial knowledge on nutrition and food literacy. CONCLUSIONS: Adolescents' recommendations highlighted multi-level, multi-component factors that influenced their ability to lead healthy lifestyles. Uptake of these recommendations by policy-makers and program developers may be of added value for lifestyle treatment targeting adolescents with obesity.


Subject(s)
Healthy Lifestyle , Patient Participation , Patient Preference , Pediatric Obesity/therapy , Policy Making , Adolescent , Body Mass Index , Canada , Deception , Diet, Healthy , Exercise , Female , Humans , Male , Marketing/standards , Parents , Pediatric Obesity/prevention & control , Qualitative Research , Schools/organization & administration
4.
Pilot Feasibility Stud ; 5: 149, 2019.
Article in English | MEDLINE | ID: mdl-31890261

ABSTRACT

BACKGROUND: Adolescents and providers can benefit from practical tools targeting lifestyle modification for obesity prevention and management. We created Conversation Cards for Adolescents© (CCAs), a patient-centered communication and behavior change tool for adolescents and providers to use in clinical practice. The purpose of our study is to (i) assess the feasibility of CCAs in a real-world, practice setting to inform full-scale trial procedures, (ii) assess user experiences of CCAs, and (iii) determine the preliminary effect of CCAs on changing behavioral and affective-cognitive outcomes among adolescents. METHODS: Starting in early 2019, this prospective study is a nested mixed-methods, theory-driven, and pragmatic pilot randomized controlled trial with a goal to enroll 50 adolescents (13-17 years old) and 9 physicians practicing at the Northeast Community Health Centre in Edmonton, Alberta, Canada. Adolescents will collaboratively set one S.M.A.R.T. (specific, measurable, attainable, realistic, timely) goal with their physician to implement over a 3-week period; however, only those randomized to the experimental group will use CCAs to inform their goal. Outcome assessments at baseline and follow-up (3 weeks post-baseline) will include behavioral, affective-cognitive, and process-related outcomes. DISCUSSION: In examining the feasibility, user experiences, and preliminary effect of CCAs, our study will add contributions to the obesity literature on lifestyle modifications among adolescents in a real-world, practice setting as well as inform the scalability of our approach for a full-scale effectiveness randomized controlled trial on behavior change. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03821896.

5.
Rev Sci Instrum ; 87(11): 11E527, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27910659

ABSTRACT

A multi-spectral line-polarization motional Stark effect (MSE-MSLP) diagnostic has been developed for the Alcator C-Mod tokamak wherein the Stokes vector is measured in multiple wavelength bands simultaneously on the same sightline to enable better polarized background subtraction. A ten-sightline, four wavelength MSE-MSLP detector system was designed, constructed, and qualified. This system consists of a high-throughput polychromator for each sightline designed to provide large étendue and precise spectral filtering in a cost-effective manner. Each polychromator utilizes four narrow bandpass interference filters and four custom large diameter avalanche photodiode detectors. Two filters collect light to the red and blue of the MSE emission spectrum while the remaining two filters collect the beam pi and sigma emission generated at the same viewing volume. The filter wavelengths are temperature tuned using custom ovens in an automated manner. All system functions are remote controllable and the system can be easily retrofitted to existing single-wavelength line-polarization MSE systems.

6.
Rev Sci Instrum ; 87(11): 11D405, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27910681

ABSTRACT

A tokamak-independent analysis suite has been developed to process data from Motional Stark Effect (mse) diagnostics. The software supports multi-spectral line-polarization mse diagnostics which simultaneously measure emission at the mse σ and π lines as well as at two "background" wavelengths that are displaced from the mse spectrum by a few nanometers. This analysis accurately estimates the amplitude of partially polarized background light at the σ and π wavelengths even in situations where the background light changes rapidly in time and space, a distinct improvement over traditional "time-interpolation" background estimation. The signal amplitude at many frequencies is computed using a numerical-beat algorithm which allows the retardance of the mse photo-elastic modulators (pem's) to be monitored during routine operation. It also allows the use of summed intensities at multiple frequencies in the calculation of polarization direction, which increases the effective signal strength and reduces sensitivity to pem retardance drift. The software allows the polarization angles to be corrected for calibration drift using a system that illuminates the mse diagnostic with polarized light at four known polarization angles within ten seconds of a plasma discharge. The software suite is modular, parallelized, and portable to other facilities.

7.
Rev Calid Asist ; 31 Suppl 2: 34-46, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27106771

ABSTRACT

OBJECTIVES: When a patient safety incident (PSI) occurs, not only the patient, but also the involved health professional can suffer. This study focused on this so-called "second victim" of a patient safety incident and aimed to examine: (1) experienced symptoms in the aftermath of a patient safety incident; (2) applied coping strategies; (3) the received versus needed support and (4) the aspects that influenced whether one becomes a second victim. MATERIALS AND METHODS: Thirty-one in-depth interviews were performed with physicians, nurses and midwives who have been involved in a patient safety incident. RESULTS: The symptoms were categorized under personal and professional impact. Both problem focused and emotion focused coping strategies were used in the aftermath of a PSI. Problem focused strategies such as performing a root cause analysis and the opportunity to learn from what happened were the most appreciated, but negative emotional responses such as repression and flight were common. Support from colleagues and supervisors who were involved in the same event, peer supporters or professional experts were the most needed. A few individuals described emotional support from the healthcare institution as unwanted. Rendered support was largely dependent on the organizational culture, a stigma remained among healthcare professionals to openly discuss patient safety incidents. Three aspects influenced the extent to which a healthcare professional became a second victim: personal, situational and organizational aspects. CONCLUSION: These findings indicated that a multifactorial approach including individual and emotional support to second victims is crucial.


Subject(s)
Accidents/psychology , Health Personnel/psychology , Medical Errors/psychology , Patient Safety , Stress, Psychological/psychology , Adaptation, Psychological , Adult , Emotions , Female , Humans , Interview, Psychological , Male , Nurse Midwives/psychology , Nurses/psychology , Organizational Culture , Physicians/psychology , Qualitative Research , Social Stigma , Social Support , Stress, Psychological/etiology
8.
Phys Rev Lett ; 111(12): 125003, 2013 Sep 20.
Article in English | MEDLINE | ID: mdl-24093268

ABSTRACT

Application of lower hybrid (LH) current drive in tokamak plasmas can induce both co- and countercurrent directed changes in toroidal rotation, depending on the core q profile. For discharges with q(0) <1, rotation increments in the countercurrent direction are observed. If the LH-driven current is sufficient to suppress sawteeth and increase q(0) above unity, the core toroidal rotation change is in the cocurrent direction. This change in sign of the rotation increment is consistent with a change in sign of the residual stress (the divergence of which constitutes an intrinsic torque that drives the flow) through its dependence on magnetic shear.

9.
Qual Saf Health Care ; 19(1): 3-8, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20172875

ABSTRACT

OBJECTIVES: In an effort to improve patient safety attitudes and skills among third-year medical students, two patient safety training sessions were added to their curriculum, complementing a previously implemented second-year curriculum on quality improvement, patient safety and teamwork. METHODS: Safety attitudes and skills were assessed before and after students completed the medicine clerkship training and were compared with historical controls. Students identified and reported on observed safety events, with their reports matched to event type and harm score with contemporaneous safety reports from University of Missouri's Patient Safety Network (PSN). Comparisons were assessed by five internal safety experts using criteria for report submission "worthiness", blame tone, target of blame and presence/strength of proposed solutions. RESULTS: Students completing the third-year safety booster conferences expressed statistically higher comfort levels with identifying the cause of an error than did the student control group (p<0.05). Medical students proposed safety interventions that were more robust than those suggested by event reporters regarding similar events within our health system (p<0.0001). The worthiness and blame tone of medical student reports were not statistically different than event reports in PSN. CONCLUSIONS: Completion of two 1-h patient safety booster conferences in the third year of medical school led to increased student comfort in safety event analysis. Students documented stronger resolution robustness scores, suggesting similar training should be offered to PSN reporters. Medical students represent an underutilised resource for identifying and proposing solutions for patient safety issues.


Subject(s)
Clinical Clerkship , Clinical Competence/standards , Curriculum , Medical Errors/prevention & control , Patient Safety , Students, Medical , Academic Medical Centers , Attitude of Health Personnel , Humans , Missouri , Patient Safety/standards , Students, Medical/psychology
10.
Qual Saf Health Care ; 18(5): 325-30, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19812092

ABSTRACT

BACKGROUND: When patients experience unexpected events, some health professionals become "second victims". These care givers feel as though they have failed the patient, second guessing clinical skills, knowledge base and career choice. Although some information exists, a complete understanding of this phenomenon is essential to design and test supportive interventions that achieve a healthy recovery. METHODS: The purpose of this article is to report interview findings with 31 second victims. After institutional review board approval, second victim volunteers representing different professional groups were solicited for private, hour-long interviews. The semistructured interview covered demographics, participant recount of event, symptoms experienced and recommendations for improving institutional support. After interviews, transcripts were analyzed independently for themes, followed by group deliberation and reflective use with current victims. RESULTS: Participants experienced various symptoms that did not differ by sex or professional group. Our analysis identified six stages that delineate the natural history of the second victim phenomenon. These are (1) chaos and accident response, (2) intrusive reflections, (3) restoring personal integrity, (4) enduring the inquisition, (5) obtaining emotional first aid and (6) moving on. We defined the characteristics and typical questions second victims are desperate to have answered during these stages. Several reported that involvement in improvement work or patient safety advocacy helped them to once again enjoy their work. CONCLUSIONS: We now believe the post-event trajectory is largely predictable. Institutional programs could be developed to successfully screen at-risk professionals immediately after an event, and appropriate support could be deployed to expedite recovery and mitigate adverse career outcomes.


Subject(s)
Health Personnel/psychology , Medical Errors/psychology , Professional-Patient Relations , Stress Disorders, Post-Traumatic/psychology , Anecdotes as Topic , Clinical Competence , Female , Humans , Interviews as Topic , Male
11.
Rev Sci Instrum ; 79(10): 10E320, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19044482

ABSTRACT

A new spatially resolving x-ray crystal spectrometer capable of measuring continuous spatial profiles of high resolution spectra (lambda/d lambda>6000) of He-like and H-like Ar K alpha lines with good spatial (approximately 1 cm) and temporal (approximately 10 ms) resolutions has been installed on the Alcator C-Mod tokamak. Two spherically bent crystals image the spectra onto four two-dimensional Pilatus II pixel detectors. Tomographic inversion enables inference of local line emissivity, ion temperature (T(i)), and toroidal plasma rotation velocity (upsilon(phi)) from the line Doppler widths and shifts. The data analysis techniques, T(i) and upsilon(phi) profiles, analysis of fusion-neutron background, and predictions of performance on other tokamaks, including ITER, will be presented.

12.
Rev Sci Instrum ; 79(10): 10F523, 2008 Oct.
Article in English | MEDLINE | ID: mdl-19044668

ABSTRACT

Many motional Stark effect diagnostics around the world make use of a calibration procedure in which the observed neutral beam is injected into a gas-filled torus with known vacuum fields. The instrument is calibrated by reconciling measured angles with vacuum magnetic reconstructions through a range of pitch angles. This in situ gas-filled torus calibration most closely approximates the working conditions of the diagnostic and includes effects such as beam and viewing geometries, beam voltages, Faraday and stress induced birefringence (in most cases) of the transmissive optics, as well as the polarimeter response. However, secondary neutrals, produced after ionization then reneutralization of a beam neutral, have been found to contaminate measured angles by emitting Balmer alpha with similar Doppler shifts and Stark polarizations as beam neutrals, but with different polarization angles. Simulation results that show spectral and angle behavior versus calibration parameters such as fill gas pressure will be presented. Data from NSTX and C-Mod will be compared to simulations results.

13.
Gene Ther ; 15(12): 902-10, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18418420

ABSTRACT

Attempts have been made to use various forms of cellular vectors to deliver therapeutic genes to diseased tissues like malignant tumours. However, this approach has proved problematic due to the poor uptake of these vectors by the target tissue. We have devised a novel way of using magnetic nanoparticles (MNPs) to enhance the uptake of such 'therapeutically armed' cells by tumours. Monocytes naturally migrate from the bloodstream into tumours, so attempts have been made to use them to deliver therapeutic genes to these sites. However, transfected monocytes injected systemically fail to infiltrate tumours in large numbers. Using a new in vitro assay for assessing monocyte extravasation, we show that the ability of transfected human monocytes to migrate across a human endothelial cell layer into a 3D tumour spheroid is markedly increased when cells are pre-loaded with MNPs and a magnetic force is applied close to the spheroid. Furthermore, systemic administration of such 'magnetic' monocytes to mice bearing solid tumours led to a marked increase in their extravasation into the tumour in the presence of an external magnet. This new magnetic targeting approach could be used to increase the targeting, and thus the efficacy, of many cell-based gene therapies in vivo.


Subject(s)
Genetic Therapy/methods , Magnetics , Monocytes/metabolism , Nanoparticles , Neoplasms/therapy , Animals , Cell Adhesion , Cell Line, Tumor , Cell Movement , Cells, Cultured , Endothelial Cells/physiology , Flow Cytometry , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Iron , Male , Mice , Mice, Nude , Microscopy, Fluorescence , Neoplasms/pathology , Neoplasms, Experimental/pathology , Neoplasms, Experimental/therapy , Phagocytosis , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Transfection , Xenograft Model Antitumor Assays
14.
Gene Ther ; 13(3): 206-15, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16307003

ABSTRACT

Although a significant negative prognostic factor, tumor hypoxia can be exploited for gene therapy. To maximize targeting within the tumor mass, we have developed synthetic gene promoters containing hypoxia-responsive elements (HREs) from the erythropoietin (Epo) gene as well as radiation-responsive CArG elements from the early growth response (Egr) 1 gene. Furthermore, to achieve high and sustained expression of the suicide gene herpes simplex virus thymidine kinase (HSVtk), our gene therapy vectors contain an expression amplification system, or 'molecular switch', based on Cre/loxP recombination. In human glioma and breast adenocarcinoma cells exposed to hypoxia and/or radiation, the HRE/CArG promoter rapidly activated Cre recombinase expression leading to selective and sustained HSVtk synthesis. Killing of transfected tumor cells was measured after incubation with the prodrug ganciclovir (GCV; converted by HSVtk into a cytotoxin). In vitro, higher and more selective GCV-mediated toxicity was achieved with the switch vectors, when compared with the same inducible promoters driving HSVtk expression directly. In tumor xenografts implanted in nude mice, the HRE/CArG-switch induced significant growth delay and tumor eradication. In conclusion, hypoxia- and radiation-activated 'molecular switch' vectors represent a promising strategy for both targeted and effective gene therapy of solid tumors.


Subject(s)
Adenoviridae/genetics , Genetic Therapy/methods , Genetic Vectors/genetics , Neoplasms/therapy , Oncolytic Virotherapy/methods , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Animals , Antiviral Agents/therapeutic use , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Cell Death , Cell Hypoxia , Combined Modality Therapy , Early Growth Response Protein 1/genetics , Erythropoietin/genetics , Ganciclovir/therapeutic use , Gene Expression Regulation, Neoplastic , Genes, Switch , Genes, Transgenic, Suicide , Genetic Engineering/methods , Genetic Vectors/administration & dosage , Genetic Vectors/radiation effects , Glioma/pathology , Glioma/therapy , Humans , Mice , Mice, Nude , Neoplasms/pathology , Promoter Regions, Genetic , Simplexvirus/enzymology , Thymidine Kinase/biosynthesis , Thymidine Kinase/metabolism , Tumor Cells, Cultured
16.
Gene Ther ; 12(12): 974-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15729368

ABSTRACT

During herpes simplex virus type 1 (HSV 1) infection, the tegument protein VP22 is exported from infected cells to the nuclei of surrounding uninfected cells. These intercellular transport characteristics have prompted the exploitation of VP22 fusion proteins for cancer gene therapy, with the goal of maximizing the bystander effect. Since solid tumors contain hypoxic cell populations that are often refractive to therapy, for efficient targeting, it would be optimal if VP22 functioned even at reduced oxygen concentrations. In the present work, VP22 activity under hypoxic conditions was examined for the first time. Plasmid-transfected human glioma U87-MG and U373-MG cells expressing VP22 fused to the green fluorescent protein (GFP) showed protein export to untransfected cells under tumor oxygenation conditions (0-5% O(2)). For suicide gene therapy, VP22 activity was demonstrated under hypoxia by coupling VP22 to the HSV thymidine kinase (HSVtk). In the presence of the prodrug ganciclovir, cell cultures expressing VP22-HSVtk showed a significant increase in toxicity compared with cells transfected with a construct containing HSVtk only, under all tested conditions. To allow effective suicide gene therapy and simultaneous visualization of therapeutic enzyme localization, a triple fusion protein GFP-HSVtk-VP22 was engineered. Functionality of all components was demonstrated under oxia and hypoxia.


Subject(s)
Central Nervous System Neoplasms/therapy , Genetic Therapy/methods , Glioma/therapy , Viral Structural Proteins/genetics , Analysis of Variance , Cell Line, Tumor , Genes, Transgenic, Suicide , Genetic Engineering , Humans , Hypoxia , Transfection/methods
17.
Curr Pharm Des ; 9(26): 2105-12, 2003.
Article in English | MEDLINE | ID: mdl-14529408

ABSTRACT

The aim of cancer gene therapy is to selectively kill malignant cells at the tumor site, by exploiting traits specific to cancer cells and/or solid tumors. Strategies that take advantage of biological features common to different tumor types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia, the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumor volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene (e.g., herpes simplex virus thymidine kinase) to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug (e.g., ganciclovir). The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumor targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance.


Subject(s)
Drug Resistance, Neoplasm , Genetic Therapy/methods , Neoplasms/therapy , Animals , Combined Modality Therapy , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/radiation effects , Humans , Neoplasms/genetics , Neoplasms/radiotherapy , Promoter Regions, Genetic , Radiotherapy, Adjuvant/methods
18.
FEMS Microbiol Ecol ; 43(2): 247-54, 2003 Mar 01.
Article in English | MEDLINE | ID: mdl-19719685

ABSTRACT

Iron oxides from the caldera of Axial Volcano, a site of hydrothermal vent activity along the Juan de Fuca Ridge, were found to consist predominantly of microbial structures in hydrated whole mounts examined using an environmental scanning electron microscope. Novel observations were made of the iron oxides revealing the spatial relationships of the bacteria within to be more consistent with microbial mats than mineral precipitates. The bacterial structures are attributed to the sheaths of Leptothrix ochracea, the stalks of Gallionella ferruginea, and the filaments of a novel iron oxidizing PV-1 strain, based on the distinctive morphological characteristics of these three bacteria. Energy dispersive X-ray spectroscopy revealed the presence and distribution of Fe, Si, and Cl on the bacterial sheaths, stalks and filaments. The iron oxides were identified by X-ray diffraction to be two-line ferrihydrite, a poorly ordered iron oxyhydroxide. Adsorption of Si in particular to two-line ferrihydrite likely contributes to its stability on the seafloor, and might also be a preservation mechanism creating microfossils of the bacterial structures encrusted with ferrihydrite. Presumptive evidence of the sub-seafloor presence of L. ochracea, G. ferruginea and PV-1 at Axial Volcano was obtained from the presence of these bacteria on a trap that had been placed within an active vent, and also in a vent fluid sample. If indeed these bacteria are present in the sub-seafloor, it may be an indication that the surface expression of iron oxide deposits at Axial Volcano is minimal in comparison to what exists beneath the seafloor.

19.
Gene Ther ; 9(20): 1396-402, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12365005

ABSTRACT

We have been developing synthetic gene promoters responsive to clinical doses of ionizing radiation (IR) for use in suicide gene therapy vectors. The crucial DNA sequences utilized are units with the consensus motif CC(A/T)(6)GG, known as CArG elements, derived from the IR-responsive Egr1 gene. In this study we have investigated the parameters needed to enhance promoter activation to radiation. A series of plasmid vectors containing different enhancer/promoters were constructed, transiently transfected into tumor cells (MCF-7 breast adenocarcinoma and U-373MG glioblastoma) and expression of a downstream reporter assayed. Results revealed that increasing the number of CArG elements, up to a certain level, increased promoter radiation-response; from a fold-induction of 1.95 +/- 0.17 for four elements to 2.74 +/- 0.17 for nine CArGs of the same sequence (for MCF-7 cells). Specific alteration of the core A/T sequences caused an even greater positive response, with fold-inductions of 1.71 +/- 0.23 for six elements of prototype sequence compared with 2.96 +/- 0.52 for one of the new sequences following irradiation. Alteration of spacing (from six to 18 nucleotides) between elements had little effect, as did the addition of an adjacent Sp1 binding site. Combining the optimum number and sequence of CArG elements in an additional enhancer was found to produce the best IR induction levels. Furthermore, the improved enhancers also performed better than the previously reported prototype when used in in vitro and in vivo experimental GDEPT. We envisage such enhancers will be used to drive suicide gene expression from vectors delivered to a tumor within an irradiated field. The modest, but tight expression described in the present study could be amplified using a molecular 'switch' system as previously described using Cre/LoxP. In combination with targeted delivery, this strategy has great potential for significantly improving the efficacy of cancer treatment in the large number of cases where radiotherapy is currently employed.


Subject(s)
Genetic Therapy/methods , Neoplasms/therapy , Promoter Regions, Genetic , Radiotherapy/methods , Adenocarcinoma/therapy , Animals , Breast Neoplasms/therapy , Enhancer Elements, Genetic , Enzyme Precursors/genetics , Female , Gene Expression , Genetic Engineering , Genetic Vectors , Glioblastoma/therapy , Humans , Mice , Mice, Nude , Neoplasms/radiotherapy , Neoplasms, Experimental/therapy , Transfection/methods , Tumor Cells, Cultured
20.
Gene Ther ; 9(20): 1403-11, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12365006

ABSTRACT

Despite being an adverse prognostic factor in radiotherapy, hypoxia represents a physiological difference that can be exploited for selective cancer gene therapy. In this study gene therapy vectors responsive to both hypoxia and ionizing radiation (IR) were developed. Gene expression was regulated by novel, synthetic promoters containing hypoxia responsive elements (HREs) from the erythropoietin (Epo), the phosphoglycerate kinase 1 (PGK1) and the vascular endothelial growth factor (VEGF) genes, and IR-responsive CArG elements from the early growth response (Egr) 1 gene. All chimeric promoters could be activated by hypoxia and/or IR-treatment, and selectively control marker gene expression in human T24 bladder carcinoma and MCF-7 mammary carcinoma cells. Importantly, enhancers containing combinations of HREs and CArG elements were able to respond to both triggering treatments, with the Epo HRE/CArG combination proving to be the most responsive and robust. The Epo HRE/CArG enhancer could effectively control a suicide gene therapy strategy by selectively sensitizing hypoxic and/or irradiated cells expressing the enzyme horseradish peroxidase (HRP) to the prodrug indole-3-acetic acid (IAA). These data indicate that the use of such chimeric promoters may effectively regulate therapeutic gene expression within the tumor microenvironment in gene therapy strategies aimed at addressing the problem of hypoxia in radiotherapy.


Subject(s)
Genetic Therapy/methods , Mammary Neoplasms, Animal/therapy , Promoter Regions, Genetic , Radiotherapy/methods , Urinary Bladder Neoplasms/therapy , Animals , Enzyme Precursors/genetics , Female , Gene Expression , Genetic Engineering , Hypoxia/genetics , Mammary Neoplasms, Animal/radiotherapy , Tumor Cells, Cultured , Urinary Bladder Neoplasms/radiotherapy
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