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BACKGROUND: The Global Digital Exemplar (GDE) Programme is a national initiative to promote digitally enabled transformation in English provider organizations. The Programme applied benefits realization management techniques to promote and demonstrate transformative outcomes. This work was part of an independent national evaluation of the GDE Programme. AIMS: We explored how benefits realization management was approached and conceptualized in the GDE Programme. METHODS: We conducted a series of 36 longitudinal case studies of provider organizations participating in the GDE Programme, 12 of which were in depth. Data collection included a combination of 628 interviews (with implementation staff in provider organizations, national programme management staff, and suppliers), 499 documents (of national and local implementation plans and lessons learned), and 190 nonparticipant observations (of national and local programme management meetings to develop insights into the broader context of benefits realization activities, tensions arising, and how these were negotiated). Data were coded drawing on a sociotechnical framework developed in related work and thematically analyzed, initially within and then across cases, with the help of NVivo 11 software. RESULTS: Most stakeholders broadly agreed with the rationale of benefits realization in the GDE Programme to show due diligence that public money was appropriately spent, and to develop an evidence base supporting the value of digitally enabled transformation. Differing national and local reporting purposes, however, created tensions. Central requirements, for progress reporting and tracking high-level benefits, had limited perceived local value and were seen to impose an unnecessary burden on provider organizations. This was accentuated by the lack of harmonization of reporting requirements to different stakeholders (which differed in content and timing). There were tensions between the desire for early evidence of outcomes and the slow processes of infrastructural change (which created problems of attribution of benefits to causes as benefits emerged gradually and over long timeframes), and also between reporting immediately visible local changes and showing how these flowed through to high level organization wide benefits (eg, in terms of health outcomes or cost savings/return on investment). The attempt to fulfill these diverging agendas and informational needs within a single reporting tool had limited success. These difficulties were mitigated by efforts to simplify reporting requirements and to support targeted collection of key national outcome measures. Although progress was hampered by an initial lack of benefits realization expertise in provider organizations, some providers subsequently retained these skills for their own change management purposes. CONCLUSIONS: There is a need to recognize the limitations and cost of benefits realization management practices in the context of healthcare digitalization where benefits may materialize over long timeframes and in unanticipated ways. Although diverse stakeholder information needs may create tensions, prior agreement about rationales for collecting information and a targeted approach to tracking local and high-level benefits may enhance local relevance, reduce perceived reporting burdens, and improve acceptance/effectiveness. A single integrated reporting mechanism is unlikely to fulfill both national and local requirements.
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Atención a la Salud , Instituciones de Salud , Humanos , Estudios LongitudinalesRESUMEN
BACKGROUND: There is currently a strong drive internationally towards creating digitally advanced healthcare systems through coordinated efforts at a national level. The English Global Digital Exemplar (GDE) programme is a large-scale national health information technology change programme aiming to promote digitally-enabled transformation in secondary healthcare provider organisations by supporting relatively digitally mature provider organisations to become international centres of excellence. AIM: To qualitatively evaluate the impact of the GDE programme in promoting digital transformation in provider organisations that took part in the programme. METHODS: We conducted a series of in-depth case studies in 12 purposively selected provider organisations and a further 24 wider case studies of the remaining organisations participating in the GDE programme. Data collected included 628 interviews, non-participant observations of 190 meetings and workshops and analysis of 9 documents. We used thematic analysis aided by NVivo software and drew on sociotechnical theory to analyse the data. RESULTS: We found the GDE programme accelerated digital transformation within participating provider organisations. This acceleration was triggered by: (1) dedicated funding and the associated requirement for matched internal funding, which in turn helped to prioritise digital transformation locally; (2) governance requirements put in place by the programme that helped strengthen existing local governance and project management structures and supported the emergence of a cadre of clinical health informatics leaders locally; and (3) reputational benefits associated with being recognised as a centre of digital excellence, which facilitated organisational buy-in for digital transformation and increased negotiating power with vendors. CONCLUSION: The GDE programme has been successful in accelerating digital transformation in participating provider organisations. Large-scale digital transformation programmes in healthcare can stimulate local progress through protected funding, putting in place governance structures and leveraging reputational benefits for participating provider organisations, around a coherent vision of transformation.
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Atención a la Salud , Hospitales , Instituciones de Salud , Personal de Salud , Humanos , Programas Nacionales de SaludRESUMEN
BACKGROUND: The English Global Digital Exemplar (GDE) program is one of the first concerted efforts to create a digital health learning ecosystem across a national health service. OBJECTIVE: This study aims to explore mechanisms that support or inhibit the exchange of interorganizational digital transformation knowledge. METHODS: We conducted a formative qualitative evaluation of the GDE program. We used semistructured interviews with clinical, technical, and managerial staff; national program managers and network leaders; nonparticipant observations of knowledge transfer activities through attending meetings, workshops, and conferences; and documentary analysis of policy documents. The data were thematically analyzed by drawing on a theory-informed sociotechnical coding framework. We used a mixture of deductive and inductive methods, supported by NVivo software, to facilitate coding. RESULTS: We conducted 341 one-on-one and 116 group interviews, observed 86 meetings, and analyzed 245 documents from 36 participating provider organizations. We also conducted 51 high-level interviews with policy makers and vendors; performed 77 observations of national meetings, workshops, and conferences; and analyzed 80 national documents. Formal processes put in place by the GDE program to initiate and reinforce knowledge transfer and learning have accelerated the growth of informal knowledge networking and helped establish the foundations of a learning ecosystem. However, formal networks were most effective when supported by informal networking. The benefits of networking were enhanced (and costs reduced) by geographical proximity, shared culture and context, common technological functionality, regional and strategic alignments, and professional agendas. CONCLUSIONS: Knowledge exchange is most effective when sustained through informal networking driven by the mutual benefits of sharing knowledge and convergence between group members in their organizational and technological setting and goals. Policy interventions need to enhance incentives and reduce barriers to sharing across the ecosystem, be flexible in tailoring formal interventions to emerging needs, and promote informal knowledge sharing.
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Ecosistema , Medicina Estatal , Personal Administrativo , Inglaterra , Humanos , ConocimientoRESUMEN
BACKGROUND: The Global Digital Exemplar (GDE) Programme was designed to promote the digitisation of hospital services in England. Selected provider organisations that were reasonably digitally-mature were funded with the expectation that they would achieve internationally recognised levels of excellence and act as exemplars ('GDE sites') and share their learning with somewhat less digitally-mature Fast Follower (FF) sites. AIMS: This paper explores how partnerships between GDE and FF sites have promoted knowledge sharing and learning between organisations. METHODS: We conducted an independent qualitative longitudinal evaluation of the GDE Programme, collecting data across 36 provider organisations (including acute, mental health and speciality), 12 of which we studied as in-depth ethnographic case studies. We used a combination of semi-structured interviews with programme leads, vendors and national policy leads, non-participant observations of meetings and workshops, and analysed national and local documents. This allowed us to explore both how inter-organisational learning and knowledge sharing was planned, and how it played out in practice. Thematic qualitative analysis, combining findings from diverse data sources, was facilitated by NVivo 11 and drew on sociotechnical systems theory. RESULTS: Formally established GDE and FF partnerships were perceived to enhance learning and accelerate adoption of technologies in most pairings. They were seen to be most successful where they had encouraged, and were supported by, informal knowledge networking, driven by the mutual benefits of information sharing. Informal networking was enhanced where the benefits were maximised (for example where paired sites had implemented the same technological system) and networking costs minimised (for example by geographical proximity, prior links and institutional alignment). Although the intervention anticipated uni-directional learning between exemplar sites and 'followers', in most cases we observed a two-way flow of information, with GDEs also learning from FFs, through informal networking which also extended to other health service providers outside the Programme. The efforts of the GDE Programme to establish a learning ecosystem has enhanced the profile of shared learning within the NHS. CONCLUSIONS: Inter-organisational partnerships have produced significant gains for both follower (FF) and exemplar (GDE) sites. Formal linkages were most effective where they had facilitated, and were supported by, informal networking. Informal networking was driven by the mutual benefits of information sharing and was optimised where sites were well aligned in terms of technology, geography and culture. Misalignments that created barriers to networking between organisations in a few cases were attributed to inappropriate choice of partners. Policy makers seeking to promote learning through centrally directed mechanisms need to create a framework that enables networking and informal knowledge transfer, allowing local organisations to develop bottom-up collaboration and exchanges, where they are productive, in an organic manner.
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Servicios de Salud , Difusión de la Información , Conocimiento , Organizaciones , Investigación Cualitativa , Inglaterra , Geografía , Grupo Paritario , TecnologíaRESUMEN
OBJECTIVE: The Global Digital Exemplar (GDE) Program is a national attempt to accelerate digital maturity in healthcare providers through promoting knowledge transfer across the English National Health Service (NHS). "Blueprints"-documents capturing implementation experience-were intended to facilitate this knowledge transfer. Here we explore how Blueprints have been conceptualized, produced, and used to promote interorganizational knowledge transfer across the NHS. MATERIALS AND METHODS: We undertook an independent national qualitative evaluation of the GDE Program. This involved collecting data using semistructured interviews with implementation staff and clinical leaders in provider organizations, nonparticipant observation of meetings, and key documents. We also attended a range of national meetings and conferences, interviewed national program managers, and analyzed a range of policy documents. Our analysis drew on sociotechnical principles, combining deductive and inductive methods. RESULTS: Data comprised 508 interviews, 163 observed meetings, and analysis of 325 documents. We found little evidence of Blueprints being adopted in the manner originally conceived by national program managers. However, they proved effective in different ways to those planned. As well as providing a helpful initial guide to a topic, we found that Blueprints served as a method of identifying relevant expertise that paved the way for subsequent discussions and richer knowledge transfers amongst provider organizations. The primary value of Blueprinting, therefore, seemed to be its role as a networking tool. Members of different organizations came together in developing, applying, and sustaining Blueprints through bilateral conversations-in some circumstances also fostering informal communities of practice. CONCLUSIONS: Blueprints may be effective in facilitating knowledge transfer among healthcare organizations, but need to be accompanied by other evolving methods, such as site visits and other networking activities, to iteratively transfer knowledge and experience.
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Hospitales , Medicina Estatal , Comunicación , Personal de Salud , HumanosRESUMEN
INTRODUCTION: Many countries are launching large-scale, digitally enabled change programmes as part of efforts to improve the quality, safety and efficiency of care. We have been commissioned to conduct an independent evaluation of a major national change programme, the Global Digital Exemplar (GDE) Programme, which aims to develop exemplary digital health solutions and encourage their wider adoption by creating a learning ecosystem across English National Health Service (NHS) provider organisations. METHODS AND ANALYSIS: This theoretically informed, qualitative, longitudinal formative evaluation comprises five inter-related work packages. We will conduct a combination of 12 in-depth and 24 broader qualitative case studies in GDE sites exploring digital transformation, local learning and mechanisms of spread of knowledge within the Programme and across the wider NHS. Data will be collected through a combination of semistructured interviews with managers, implementation staff (clinical and non-clinical), vendors and policymakers, plus non-participant observations of meetings, site visits, workshops and documentary analysis of strategic local and national plans. Data will be analysed through inductive and deductive methods, beginning with in-depth case study sites and testing the findings against data from the wider sample and national stakeholders. ETHICS AND DISSEMINATION: This work is commissioned as part of a national change programme and is therefore a service evaluation. We have ethical approval from the University of Edinburgh. Results will be disseminated at six monthly intervals to national policymakers, and made available via our publicly accessible website. We will also identify lessons for the management and evaluation of large-scale evolving digital health change programmes that are of international relevance.
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Ecosistema , Medicina Estatal , Humanos , Estudios Longitudinales , Investigación CualitativaRESUMEN
BACKGROUND: Hospitals worldwide are developing ambitious digital transformation programs as part of broader efforts to create digitally advanced health care systems. However, there is as yet no consensus on how best to characterize and assess digital excellence in hospitals. OBJECTIVE: Our aim was to develop an international agreement on a defined set of technological capabilities to assess digital excellence in hospitals. METHODS: We conducted a two-stage international modified electronic Delphi (eDelphi) consensus-building exercise, which included a qualitative analysis of free-text responses. In total, 31 international health informatics experts participated, representing clinical, academic, public, and vendor organizations. RESULTS: We identified 35 technological capabilities that indicate digital excellence in hospitals. These are divided into two categories: (a) capabilities within a hospital (n=20) and (b) capabilities enabling communication with other parts of the health and social care system, and with patients and carers (n=15). The analysis of free-text responses pointed to the importance of nontechnological aspects of digitally enabled change, including social and organizational factors. Examples included an institutional culture characterized by a willingness to transform established ways of working and openness to risk-taking. The availability of a range of skills within digitization teams, including technological, project management and business expertise, and availability of resources to support hospital staff, were also highlighted. CONCLUSIONS: We have identified a set of criteria for assessing digital excellence in hospitals. Our findings highlight the need to broaden the focus from technical functionalities to wider digital transformation capabilities.
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Atención a la Salud/normas , Hospitales/normas , Telemedicina/métodos , Técnica Delphi , HumanosRESUMEN
BACKGROUND: Attempts to achieve digital transformation across the health service have stimulated increasingly large-scale and more complex change programmes. These encompass a growing range of functions in multiple locations across the system and may take place over extended timeframes. This calls for new approaches to evaluate these programmes. MAIN BODY: Drawing on over a decade of conducting formative and summative evaluations of health information technologies, we here build on previous work detailing evaluation challenges and ways to tackle these. Important considerations include changing organisational, economic, political, vendor and markets necessitating tracing of evolving networks, relationships, and processes; exploring mechanisms of spread; and studying selected settings in depth to understand local tensions and priorities. CONCLUSIONS: Decision-makers need to recognise that formative evaluations, if built on solid theoretical and methodological foundations, can help to mitigate risks and help to ensure that programmes have maximum chances of success.
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Difusión de Innovaciones , Informática Médica/organización & administración , Modelos Teóricos , Estudios de Evaluación como Asunto , HumanosRESUMEN
Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease- and treatment-related neurotoxicities appear to be additive, targeting disease-related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus (HPV)-related head and neck cancer. This model has the advantage of being mildly aggressive and not causing cachexia or weight loss. We previously showed that this tumor leads to increased IL-6, IL-1ß, and TNF-α expression in the liver and increased IL-1ß expression in the brain. The current study confirmed these features and demonstrated that the tumor itself exhibits high inflammatory cytokine expression (e.g., IL-6, IL-1ß, and TNF-α) compared to healthy tissue. While there is a clear relationship between cytokine levels and behavioral deficits in this model, the behavioral changes are surprisingly mild. Therefore, we sought to confirm the relationship between behavior and inflammation by amplifying the effect using a low dose of lipopolysaccharide (LPS, 0.1mg/kg). In tumor-bearing mice LPS induced deficits in nest building, tail suspension, and locomotor activity approximately 24h after LPS. However, these mice did not display an exacerbation of LPS-induced weight loss, anorexia, or anhedonia. Further, while heightened serum IL-6 was observed there was minimal priming of liver or brain cytokine expression. Next we sought to inhibit tumor-induced burrowing deficits by reducing inflammation using minocycline. Minocycline (â¼50mg/kg/day in drinking water) was able to attenuate tumor-induced inflammation and burrowing deficits. These data provide evidence in favor of an inflammatory-like mechanism for the behavioral alterations associated with tumor growth in a syngeneic murine model of HPV-related head and neck cancer. However, the inflammatory state and behavioral changes induced by this tumor clearly differ from other forms of inflammation-induced sickness behavior.
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Citocinas/metabolismo , Neoplasias de Cabeza y Cuello/inmunología , Conducta de Enfermedad , Papillomaviridae , Animales , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , NeuroinmunomodulaciónRESUMEN
We explore the relationship among experimental design, parameter estimation, and systematic error in sloppy models. We show that the approximate nature of mathematical models poses challenges for experimental design in sloppy models. In many models of complex biological processes it is unknown what are the relevant physical mechanisms that must be included to explain system behaviors. As a consequence, models are often overly complex, with many practically unidentifiable parameters. Furthermore, which mechanisms are relevant/irrelevant vary among experiments. By selecting complementary experiments, experimental design may inadvertently make details that were ommitted from the model become relevant. When this occurs, the model will have a large systematic error and fail to give a good fit to the data. We use a simple hyper-model of model error to quantify a model's discrepancy and apply it to two models of complex biological processes (EGFR signaling and DNA repair) with optimally selected experiments. We find that although parameters may be accurately estimated, the discrepancy in the model renders it less predictive than it was in the sloppy regime where systematic error is small. We introduce the concept of a sloppy system-a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. We explore the limits of accurate parameter estimation in sloppy systems and argue that identifying underlying mechanisms controlling system behavior is better approached by considering a hierarchy of models of varying detail rather than focusing on parameter estimation in a single model.
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Modelos Biológicos , Proyectos de Investigación , Algoritmos , Animales , Reparación del ADN , Receptores ErbB , Cinética , Ratones , Transducción de Señal , Irradiación Corporal TotalRESUMEN
The contents of the lab notebooks of H.R. Withers have been digitized and stored as 23 excel files, a total of approximately 45 megabytes. A procedure is described whereby those interested may gain access to the data.
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Archivos , Oncología por Radiación/historia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Sistemas en Línea , Radiobiología/historia , Investigación Biomédica Traslacional/historia , Estados UnidosRESUMEN
The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Genes Mitocondriales , Neoplasias de Cabeza y Cuello/terapia , Conducta de Enfermedad/efectos de los fármacos , Conducta de Enfermedad/efectos de la radiación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Encéfalo/efectos de la radiación , Quimioradioterapia , Citocinas/metabolismo , Expresión Génica/efectos de los fármacos , Expresión Génica/efectos de la radiación , Genes Mitocondriales/efectos de los fármacos , Genes Mitocondriales/efectos de la radiación , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/fisiopatología , Conducta de Enfermedad/fisiología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Hígado/efectos de la radiación , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de la radiación , Motivación/efectos de los fármacos , Motivación/fisiología , Motivación/efectos de la radiación , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Actividad Motora/efectos de la radiación , Trasplante de Neoplasias , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/fisiopatología , Neoplasias Orofaríngeas/terapia , Papillomaviridae , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
Polymer complex constructed from WR 2721 and poly(hydroxyoxyethylene phosphate) was synthesized. The structure of complex formed was elucidated by (1)H-, (13)C, (31)P NMR and FT-IR spectroscopy. The radioprotector was immobilized via ionic bonds. Radioprotective efficacy was evaluated by clonal survival of stem cells in crypts of mouse small intestine, and incidence and latency of the acute radiation induced bone marrow syndrome. Protection factors were assessed for WR 2721 and for the polymer complex. Protection factors for the polymer complex ranged from 2.6 for intestinal stem cell survival to 1.35 for 30 day survival (LD50) following whole body radiation exposure. In all cases, the polymer complex was a significantly better radiation protector than the parent compound.
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Amifostina/síntesis química , Amifostina/farmacología , Polímeros/síntesis química , Polímeros/farmacología , Protectores contra Radiación/síntesis química , Protectores contra Radiación/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Intestino Delgado/efectos de los fármacos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Ratones , Ratones Endogámicos C3H , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Células Madre/efectos de los fármacosRESUMEN
INTRODUCTION: Traditional clonogenic survival and high throughput colorimetric assays are inadequate as drug screens to identify novel radiation sensitizers. We developed a method that we call the high content clonogenic survival assay (HCSA) that will allow screening of drug libraries to identify candidate radiation sensitizers. METHODS: Drug screen using HCSA was done in 96 well plates. After drug treatment, irradiation, and incubation, colonies were stained with crystal violet and imaged on the INCell 6000 (GE Health). Colonies achieving 50 or more cells were enumerated using the INCell Developer image analysis software. A proof-of-principle screen was done on the KRAS mutant lung cancer cell line H460 and a Custom Clinical Collection (146 compounds). RESULTS: Multiple drugs of the same class were found to be radiation sensitizers and levels of potency seemed to reflect the clinical relevance of these drugs. For instance, several PARP inhibitors were identified as good radiation sensitizers in the HCSA screen. However, there were also a few PARP inhibitors not found to be sensitizing that have either not made it into clinical development, or in the case of BSI-201, was proven to not even be a PARP inhibitor. We discovered that inhibitors of pathways downstream of activated mutant KRAS (PI3K, AKT, mTOR, and MEK1/2) sensitized H460 cells to radiation. Furthermore, the potent MEK1/2 inhibitor tramenitib selectively enhanced radiation effects in KRAS mutant but not wild-type lung cancer cells. CONCLUSIONS: Drug screening for novel radiation sensitizers is feasible using the HCSA approach. This is an enabling technology that will help accelerate the discovery of novel radiosensitizers for clinical testing.
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Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Ensayos de Selección de Medicamentos Antitumorales/métodos , Neoplasias Pulmonares/radioterapia , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Antineoplásicos/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Masculino , Ratones , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ensayo de Tumor de Célula Madre , Proteínas ras/genéticaRESUMEN
PURPOSE: To test the appropriateness of the linear-quadratic (LQ) model to describe survival of jejunal crypt clonogens after split doses with variable (small 1-6 Gy, large 8-13 Gy) first dose, as a model of its appropriateness for both small and large fraction sizes. METHODS: C3Hf/KamLaw mice were exposed to whole body irradiation using 300 kVp X-rays at a dose rate of 1.84 Gy/min, and the number of viable jejunal crypts was determined using the microcolony assay. 14 Gy total dose was split into unequal first and second fractions separated by 4 h. Data were analyzed using the LQ model, the lethal potentially lethal (LPL) model, and a repair-saturation (RS) model. RESULTS: Cell kill was greater in the group receiving the larger fraction first, creating an asymmetry in the plot of survival vs size of first dose, as opposed to the prediction of the LQ model of a symmetric response. There was a significant difference in the estimated ßs (higher ß after larger first doses), but no significant difference in the αs, when large doses were given first vs small doses first. This difference results in underestimation (based on present data by approximately 8%) of isoeffect doses using LQ model parameters based on small fraction sizes. While the LPL model also predicted a symmetric response inconsistent with the data, the RS model results were consistent with the observed asymmetry. CONCLUSION: The LQ model underestimates doses for isoeffective crypt-cell survival with large fraction sizes (in the present setting, >9 Gy).
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Fraccionamiento de la Dosis de Radiación , Radiocirugia , Animales , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Modelos Lineales , Ratones , Ratones Endogámicos C3H , Dosificación RadioterapéuticaRESUMEN
PURPOSE: To test whether a cyclooxygenase-2 inhibitor (celecoxib) could reduce mortality resulting from radiation-induced pneumonitis. METHODS AND MATERIALS: Celecoxib was given to mice twice daily for 40 consecutive days starting on the day of local thoracic irradiation (LTI) or 40 or 80 days later. C3Hf/KamLaw mice were observed for morbidity, and time to death was determined. Results were analyzed using the Cox proportional hazards model. RESULTS: Timing of celecoxib relative to LTI determined efficacy. A significant reduction in time to death was achieved only when celecoxib was started 80 days after LTI, corresponding to the time when pneumonitis is expressed. For these mice the reduction in mortality was quantified as a hazard ratio for mortality of treated vs untreated of 0.36 (95% confidence interval [CI] 0.24-0.53), thus significantly less than 1.0. Correspondingly, the median lethal dose for treated mice (12.9 Gy; 95% CI 12.55-13.25 Gy) was significantly (P=.026) higher than for untreated mice (12.4 Gy; 95% CI 12.2-12.65 Gy). CONCLUSIONS: Celecoxib significantly reduced lung toxicity when administered months after LTI when the deleterious effects of radiation were expressed. The schedule-dependent reduction in fatal pneumonitis suggests that celecoxib could be clinically useful by reintroduction of treatment months after completion of radiation therapy. These findings may be important for designing clinical trials using cyclooxygenase-2 inhibitors to treat radiation-induced lung toxicity as a complement to concurrent radiation therapy of lung cancers.
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Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Pirazoles/administración & dosificación , Neumonitis por Radiación/prevención & control , Sulfonamidas/administración & dosificación , Animales , Celecoxib , Intervalos de Confianza , Relación Dosis-Respuesta en la Radiación , Esquema de Medicación , Femenino , Dosificación Letal Mediana , Ratones , Ratones Endogámicos C3H , Modelos de Riesgos Proporcionales , Neumonitis por Radiación/mortalidad , Tiempo de TratamientoRESUMEN
BACKGROUND: Many prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells. METHODS: The radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib's ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay. RESULTS: Clonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone. CONCLUSIONS: We conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.