RESUMO
Synaptotagmin (Syt) VII is a ubiquitously expressed member of the Syt family of Ca2+ sensors. It is present on lysosomes in several cell types, where it regulates Ca2+-dependent exocytosis. Because [Ca2+]i and exocytosis have been associated with phagocytosis, we investigated the phagocytic ability of macrophages from Syt VII-/- mice. Syt VII-/- macrophages phagocytose normally at low particle/cell ratios but show a progressive inhibition in particle uptake under high load conditions. Complementation with Syt VII rescues this phenotype, but only when functional Ca2+-binding sites are retained. Reinforcing a role for Syt VII in Ca2+-dependent phagocytosis, particle uptake in Syt VII-/- macrophages is significantly less dependent on [Ca2+]i. Syt VII is concentrated on peripheral domains of lysosomal compartments, from where it is recruited to nascent phagosomes. Syt VII recruitment is rapidly followed by the delivery of Lamp1 to phagosomes, a process that is inhibited in Syt VII-/- macrophages. Thus, Syt VII regulates the Ca2+-dependent mobilization of lysosomes as a supplemental source of membrane during phagocytosis.
Assuntos
Cálcio/metabolismo , Proteínas de Membrana Lisossomal/metabolismo , Macrófagos/metabolismo , Fagocitose , Fagossomos/metabolismo , Sinaptotagminas/metabolismo , Animais , Membrana Celular/química , Membrana Celular/metabolismo , Células Cultivadas , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Lisossomos/metabolismo , Camundongos , Camundongos Knockout , Sinaptotagminas/genéticaRESUMO
Purpose: This update will highlight a few of the projects funded by the National Eye Institute (NEI) Audacious Goals Initiative for Regenerative Medicine (AGI) and show their potential to advance regenerative medicine strategies and increase our understanding of the pathobiology of retinal disease. Methods: We summarize the recent updates from a talk given to the scientific community about the progress of various AGI-funded projects. Results: NEI is catalyzing the translation of ocular stem cell therapies with its AGI program. Since 2015, NEI has organized 3 consortia to catalyze stem cell-based therapies. The first focuses on developing functional imaging technologies that can enable noninvasive in vivo monitoring of activity of individual retinal neurons. The second consortium is identifying novel neural regeneration factors in the visual system. The third, funded in September of 2018, aims to generate translation-enabling models that mimic human eye disease and will evaluate the survival and integration of regenerated neurons in the visual system. Conclusions: To date, 3 AGI consortia have catalyzed research in areas that will enable clinical trials for novel regenerative medicine approaches. With the first of the 3 consortia entering the final year of funding, some of these AGI-funded projects stand ready for deployment in the scientific and medical communities.
Assuntos
Medicina Regenerativa , Transplante de Células-Tronco , Humanos , National Eye Institute (U.S.) , Estados UnidosRESUMO
Eight years since the launch of the National Eye Institute Audacious Goals Initiative for Regenerative Medicine, real progress has been made in the effort to restore vision by replacing retinal neurons. Although challenges remain, the infrastructure, tools, and preclinical models to support clinical studies in humans are being prepared. Building on the pioneering trials that are replacing the retinal pigment epithelium, it is expected that by the end of this decade first-in-human trials for the replacement of retinal neurons will be initiated.
Assuntos
National Eye Institute (U.S.) , Medicina Regenerativa , Humanos , Objetivos , Estados UnidosRESUMO
Purpose: To review past and current National Eye Institute (NEI)-supported age-related macular degeneration (AMD) activities and initiatives and preview upcoming coordinated efforts for studying AMD. Methods: We conducted and summarized a portfolio analysis and literature review of NEI intramural and extramural AMD activities. Results: The NEI supports a broad range of AMD research, both by individual independent investigators as well as through networks and consortia. The International AMD Genomics Consortium, Age-Related Eye Disease Study, Age-Related Eye Disease Study 2 (AREDS2), and Comparison of AMD Treatments Trial legacy work probed the complex genetics, clinical presentation, and standards of patient care, respectively. The NEI AMD Pathobiology Working Group identified gaps and opportunities for future research efforts. The AMD Ryan Initiative Study and clinical trials testing the efficacies of minocycline to modulate retinal microglia activity and induced pluripotent stem cells-derived retinal pigmented epithelium (RPE) patch implants to rescue photoreceptor cell death are among the future directions for NEI-supported AMD research. Finally, NEI commissioned the creation of AREDS2 participant-derived induced pluripotent stem cell (iPSC) lines linked to their associated genomic and phenotypic datasets. These datasets will also be linked to the data obtained using their associated iPSC-derived cells (RPE, retina, choroid) and made publicly available. Conclusions: Investments by NEI for AMD research will continue to provide invaluable resources to investigators committed to addressing this complex blinding disease and other retinal degenerative diseases. Translational Relevance: NEI now stands poised to expand the resources available to clinical investigators to uncover disease mechanisms and move experimental therapies into clinical trials.
Assuntos
Células-Tronco Pluripotentes Induzidas , Degeneração Macular , Degeneração Retiniana , Humanos , Degeneração Macular/genética , National Eye Institute (U.S.) , Retina , Estados Unidos/epidemiologiaRESUMO
In this study, we describe efforts by the National Eye Institute (NEI) and National Center for Advancing Translational Science (NCATS) to catalyze advances in 3-dimensional (3-D) ocular organoid and microphysiological systems (MPS). We reviewed the recent literature regarding ocular organoids and tissue chips. Animal models, 2-dimensional cell culture models, and postmortem human tissue samples provide the vision research community with insights critical to understanding pathophysiology and therapeutic development. The advent of induced pluripotent stem cell technologies provide researchers with enticing new approaches and tools that augment study in more traditional models to provide the scientific community with insights that have previously been impossible to obtain. Efforts by the National Institutes of Health (NIH) have already accelerated the pace of scientific discovery, and recent advances in ocular organoid and MPS modeling approaches have opened new avenues of investigation. In addition to more closely recapitulating the morphologies and physiological responses of in vivo human tissue, key breakthroughs have been made in the past year to resolve long-standing scientific questions regarding tissue development, molecular signaling, and pathophysiological mechanisms that promise to provide advances critical to therapeutic development and patient care. 3-D tissue culture modeling and MPS offer platforms for future high-throughput testing of therapeutic candidates and studies of gene interactions to improve models of complex genetic diseases with no well-defined etiology, such as age-related macular degeneration and Fuchs' dystrophy.
Assuntos
Desenvolvimento de Medicamentos , Células-Tronco Pluripotentes Induzidas/metabolismo , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Soluções Oftálmicas/síntese química , Organoides/metabolismo , Animais , Humanos , Células-Tronco Pluripotentes Induzidas/química , Soluções Oftálmicas/química , Organoides/química , Engenharia TecidualRESUMO
We have previously shown that vaccination with purified Entamoeba histolytica Gal/GalNAc lectin or recombinant subunits can protect mice from intestinal amebiasis upon intracecal challenge. In this study, we demonstrated with adoptive-transfer experiments that this lectin vaccine protection is mediated by T cells but not serum. The cell-mediated immune (CMI) response was characterized by significant gamma interferon (IFN-gamma), interleukin 12 (IL-12), IL-2, IL-10, and IL-17 production. To move toward a human vaccine, we switched to a recombinant protein and tested a range of adjuvants and routes appropriate for humans. We found that subcutaneous delivery of LecA with IDRI's adjuvant system EM014 elicited a potent Th1-type CMI profile and provided significant protection, as measured by culture negativity (79% efficacy); intranasal immunization with cholera toxin provided 56% efficacy; and alum induced a Th2-type response that protected 62 to 68% of mice. Several antibody and CMI cytokine responses were examined for correlates of protection, and prechallenge IFN-gamma(+) or IFN-gamma-, IL-2-, and tumor necrosis factor alpha-triple-positive CD4 cells in blood were statistically associated with protection. To test the role of IFN-gamma in LecA-mediated protection, we neutralized IFN-gamma in LecA-immunized mice and found that it abrogated the protection conferred by vaccination. These data demonstrate that CMI is sufficient for vaccine protection from intestinal amebiasis and reveal an important role for IFN-gamma, even in the setting of alum.
Assuntos
Antígenos Glicosídicos Associados a Tumores/imunologia , Disenteria Amebiana/prevenção & controle , Entamoeba histolytica/imunologia , Interferon gama/fisiologia , Vacinas Protozoárias/imunologia , Linfócitos T/imunologia , Vacinas Sintéticas/imunologia , Adesinas Bacterianas/fisiologia , Adjuvantes Imunológicos/administração & dosagem , Transferência Adotiva , Animais , Anticorpos Antiprotozoários/sangue , Masculino , Camundongos , Camundongos Endogâmicos CBARESUMO
OBJECTIVES: We sought to better understand the challenges of communicating with the public about emerging health threats, particularly threats involving toxic chemicals, biological agents, and radioactive materials. METHODS: At the request of the Centers for Disease Control and Prevention, we formed an interdisciplinary consortium of investigative teams from 4 schools of public health. Over 2 years, the investigative teams conducted 79 focus group interviews with 884 participants and individual cognitive response interviews with 129 respondents, for a total sample of 1013 individuals. The investigative teams systematically compared their results with other published research in public health, risk communication, and emergency preparedness. RESULTS: We found limited public understanding of emerging biological, chemical, and radioactive materials threats and of the differences between them; demand for concrete, accurate, and consistent information about actions needed for protection of self and family; active information seeking from media, local authorities, and selected national sources; and areas in which current emergency messaging can be improved. CONCLUSIONS: The public will respond to a threat situation by seeking protective information and taking self-protective action, underlining the critical role of effective communication in public health emergencies.
Assuntos
Atitude Frente a Saúde , Comunicação , Educação em Saúde/organização & administração , Avaliação das Necessidades/organização & administração , Prática de Saúde Pública , Adulto , Centers for Disease Control and Prevention, U.S. , Doenças Transmissíveis Emergentes/prevenção & controle , Planejamento em Desastres/organização & administração , Feminino , Grupos Focais , Humanos , Disseminação de Informação/métodos , Masculino , Meios de Comunicação de Massa , Desenvolvimento de Programas , Pesquisa Qualitativa , Liberação Nociva de Radioativos/prevenção & controle , Medição de Risco , Faculdades de Saúde Pública , Autocuidado , Inquéritos e Questionários , Terrorismo/prevenção & controle , Estados UnidosRESUMO
One of the most innovative aspects of NCRP Report No. 138 (Management of Terrorist Incidents Involving Radioactive Material) was the high priority it accorded to psychosocial and communication issues. While previous discussions of radiological and nuclear terrorism had occasionally referred to these topics, NCRP Report No. 138 was the first report of its kind to recognize the profound challenges posed by these issues and to place them at the heart of preparedness and response efforts. In the years since the report's release, a host of important developments have taken place in relation to psychosocial and communication issues. This paper reviews key changes and advances in five broad areas: (1) training exercises, (2) policy and guidance development, (3) findings on hospital and clinician needs, (4) survey research on public perceptions of radiological terrorism, and (5) risk communication for radiological and nuclear terrorism situations. The article concludes with a discussion of continuing psychosocial and communication challenges, including critical areas needing further attention as the nation moves to meet the threat of terrorism involving radioactive materials.
Assuntos
Comunicação , Guerra Nuclear/psicologia , Proteção Radiológica , Liberação Nociva de Radioativos/psicologia , Terrorismo , Política de Saúde , Humanos , PercepçãoRESUMO
With the threat posed by terrorism involving radioactive materials now high on the nation's agenda, local, state, and federal agencies are moving to enhance preparedness and response capabilities. Crucial to these efforts is the development of effective risk communication strategies. This article reports findings from an ongoing study of risk communication issues in nuclear/radiological terrorism situations. It is part of a larger CDC-funded effort that aims to better understand communication challenges associated with weapons of mass destruction terrorism incidents. Presented here are formative research findings from 16 focus groups (n = 163) in which a multi-part, hypothetical radioactive materials terrorism situation was discussed. Twelve of the focus groups were carried out with members of the general public (drawn from a variety of ethnic backgrounds and geographic locations), and four groups were composed of first responders, hospital emergency department personnel, and public health professionals. One aim of the focus groups was to elicit detailed information on people's knowledge, views, perceptions, reactions, and concerns related to a nuclear/radiological terrorism event, and to better understand people's specific information needs and preferred information sources. A second aim was to pretest draft informational materials prepared by CDC and NIOSH. Key findings for the public and professional groups are presented, and the implications of the research for developing messages in radiological/nuclear terrorism situations are explored.
Assuntos
Comunicação , Lesões por Radiação/prevenção & controle , Proteção Radiológica , Terrorismo , Planejamento em Desastres , Grupos Focais , Humanos , Sistemas de Informação , Saúde PúblicaRESUMO
The United States has not suffered significant psychosocial or medical consequences from the use of biological weapons within its territories. This has contributed to a "natural" state of denial at the community level. This denial could amplify the sense of crisis, anxiety, fear, chaos, and disorder that would accompany such a bioterrorist event. A key part of primary prevention involves counteracting this possibility before an incident occurs. Doing so will require realistic information regarding the bioterrorism threat followed by the development of a planned response and regular practice of that response. Unlike in natural disasters or other situations resulting in mass casualties, emergency department physicians or nurses and primary care physicians (working in concert with epidemiologic agencies), rather than police, firemen, or ambulance personnel, will be most likely to first identify the unfolding disaster associated with a biological attack. Like community leaders, this group of medical responders must be aware of its own susceptibility to mental health sequelae and performance decrement as the increasing demands of disaster response outpace the availability of necessary resources. A bioterrorist attack will necessitate treatment of casualties who experience neuropsychiatric symptoms and syndromes. Although symptoms may result from exposure to infection with specific biological agents, similar symptoms may result from the mere perception of exposure or arousal precipitated by fear of infection, disease, suffering, and death. Conservative use of psychotropic medications may reduce symptoms in exposed and uninfected individuals, as may cognitive-behavioral interventions. Clear, consistent, accessible, reliable, and redundant information (received from trusted sources) will diminish public uncertainty about the cause of symptoms that might otherwise prompt persons to seek unnecessary treatment. Training and preparation for contingencies experienced in an attack have the potential to enhance delivery of care. Initiating supportive social, psychotherapeutic, and psychopharmacologic treatments judiciously for symptoms and syndromes known to accompany the traumatic stress response can aid the efficient treatment of some patients and reduce long-term morbidity in affected individuals. Preventive strategies and planning must take into account the idea that specific groups within the population are at higher risk for psychiatric morbidity. First responders comprise one group at psychologic risk in this situation, and healthcare providers comprise another. These and other high-risk groups will benefit from the same supportive interventions developed for the community as a whole.
Assuntos
Bioterrorismo , Planejamento em Desastres , Serviços de Emergência Psiquiátrica , Transtornos de Estresse Pós-Traumáticos/terapia , Serviços Comunitários de Saúde Mental/organização & administração , Humanos , Estresse Psicológico/prevenção & controle , Estados UnidosRESUMO
When a disaster strikes, parents are quick to seek out the medical advice and reassurance of their primary care physician, pediatrician, or in the case of an emergency, an emergency department physician. As physicians often are the first line of responders following a disaster, it is important that they have a thorough understanding of children's responses to trauma and disaster and of recommended practices for screening and intervention. In collaboration with mental health professionals, the needs of children and families can be addressed. Policy-makers and systems of care hold great responsibility for resource allocation, and also are well-placed to understand the impact of trauma and disaster on children and children's unique needs in such situations.
Assuntos
Serviços de Saúde da Criança/organização & administração , Desastres , Serviços Médicos de Emergência/organização & administração , Transtornos de Estresse Traumático/terapia , Terrorismo , Criança , Planejamento em Desastres , Humanos , Modelos Organizacionais , Estados UnidosRESUMO
In response to the March 2011 earthquake-tsunami disaster and the Fukushima Dai-ichi nuclear accident, a special nongovernmental Radiological Emergency Assistance Mission flew to Japan from the United States. Invited by one of Japan's largest hospital and healthcare groups and facilitated by a New York-based international disaster relief organization, the mission included an emergency physician, a health physicist, and a disaster management specialist. During the 10 d mission, team members conducted fieldwork in areas affected by the earthquake, tsunami, and nuclear accident; went to cities and towns in the 20-30 km Emergency Evacuation Preparation Zone around the damaged nuclear plant; visited other communities affected by the nuclear accident; went to evacuation shelters; met with mayors and other local officials; met with central government officials; exchanged observations, experiences, and information with Japanese medical, emergency response, and disaster management colleagues; and provided radiological information and training to more than 1,100 Japanese hospital and healthcare personnel and first responders. The mission produced many insights with potential relevance for radiological/nuclear emergency preparedness and response. The first "lessons learned" were published in December 2011. Since that time, additional broad insights from the mission and mission followup have been identified. Five of these new lessons, which focus primarily on community impacts and responses and public communication issues, are presented and discussed in this article.
Assuntos
Acidente Nuclear de Fukushima , Organizações , Fatores Etários , Criança , Comunicação , Gráficos por Computador , Mão de Obra em Saúde , Humanos , Mapas como Assunto , Fatores de TempoRESUMO
It is now widely recognized that effective communication is a crucial element in radiological/nuclear terrorism preparedness. Whereas in the past, communication and information issues were sometimes viewed as secondary in comparison with technical concerns, today the need to improve risk communication, public information, and emergency messaging is seen as a high priority. The process of improving radiological/nuclear terrorism risk communication can be conceptualized as occurring in four overlapping phases. The first phase involves the recognition that communication and information issues will be pivotal in shaping how a radiological/nuclear terrorism incident unfolds and in determining its outcome. This recognition has helped shape the second phase, in which various research initiatives have been undertaken to provide an empirical basis for improved communication. In the third and most recent phase, government agencies, professional organizations and others have worked to translate research findings into better messages and informational materials. Like the first and second phases, the third phase is still unfolding. The fourth phase in risk communication for radiological/nuclear terrorism-a mature phase-is only now just beginning. Central to this phase is a developing understanding that for radiological/nuclear terrorism risk communication to be fully effective, it must go beyond crafting better messages and materials (as essential as that may be). This emerging fourth phase seeks to anchor radiological/nuclear communication in a broader approach: one that actively engages and partners with the public. In this article, each of the four stages is discussed, and future directions for improving radiological/nuclear terrorism risk communication are explored.
Assuntos
Comunicação , Guerra Nuclear , Proteção Radiológica/métodos , Liberação Nociva de Radioativos/prevenção & controle , Terrorismo , Planejamento em Desastres/métodos , Serviços Médicos de Emergência , Órgãos Governamentais/organização & administração , Humanos , Lesões por Radiação/prevenção & controle , Medição de Risco/métodosRESUMO
On March 11, 2011, the eastern portion of Japan was struck by a massive earthquake and tsunami that killed more than 15,700 people, left thousands of others hurt or missing, and caused widespread destruction. In addition, the Great East Japan Disaster seriously damaged the Fukushima Dai-ichi nuclear power station, knocking out power, severely affecting communications, and causing a loss of cooling to some reactor cores. Significant quantities of radioactive materials were released, a "no go" zone was created around the crippled reactors, and thousands of people were evacuated. With concern about the radiological emergency growing, one of Japan's largest hospital and healthcare groups issued a request for assistance to a U.S.-based international disaster relief organization. After consultations with the Japanese, a special Radiological Emergency Assistance Mission was assembled. The mission, which traveled to Japan in April 2011, had several aims: (1) to rapidly assess the situation on the ground, (2) to exchange information, experiences, and insights with Japanese colleagues, and (3) to provide radiological information and practical refresher training to Japanese healthcare professionals and first responders. In addition to achieving these aims and laying the groundwork for future cooperation, the mission produced dozens of insights and lessons. These have potential relevance not only for future large-scale radiation accidents, but also for radiological and nuclear terrorism situations. They also have more general relevance for emergency planning, preparedness, and response. In this article, several of the most salient insights and lessons are highlighted.
Assuntos
Planejamento em Desastres/organização & administração , Terremotos , Missões Médicas , Liberação Nociva de Radioativos , Tsunamis , Humanos , Cooperação Internacional , Japão , Centrais Nucleares , Estados UnidosRESUMO
A nuclear detonation in a US city would have profound psychological, social, and behavioral effects. This article reviews the scientific literature on human responses to radiation incidents and disasters in general, and examines potential behavioral health care provider (BHCP) contributions in the hours and days after a nuclear detonation. In the area directly affected by the blast, the immediate overarching goal of BHCP interventions is the support of lifesaving activities and the prevention of additional casualties from fallout. These interventions include 6 broad categories: promoting appropriate protective actions, discouraging dangerous behaviors, managing patient/survivor flow to facilitate the best use of scarce resources, supporting first responders, assisting with triage, and delivering palliative care when appropriate. At more distant sites, BHCP should work with medical providers to support hospitalized survivors of the detonation. Recommendations are also made on BHCP interventions later in the response phase and during recovery.
Assuntos
Medicina do Comportamento , Atenção à Saúde , Planejamento em Saúde , Comportamento de Massa , Armas Nucleares , Liberação Nociva de Radioativos/psicologia , Cidades , Desastres , Medo , Humanos , Incidentes com Feridos em Massa , Serviços de Saúde Mental/organização & administração , Cuidados Paliativos , Papel Profissional , Cinza Radioativa , Condições Sociais , Terrorismo , Triagem , Estados UnidosRESUMO
Synaptotagmin VII (Syt VII) is a Ca(2+) sensing molecule that regulates lysosomal exocytosis in several cell types. In macrophages (MØ), Syt VII is required for efficient uptake of large particle loads, by promoting the delivery of lysosomal membrane to phagocytic cups. Here we compare the phagocytic capacity of bone marrow-derived MØs and dendritic cells (DC), and show that the requirement for Syt VII correlates with the unique ability of MØs for continuous phagocytosis. In contrast to MØs, Syt VII(+/+) and Syt VII(-/-) immature DCs show similar levels of initial phagocytosis, followed by a marked decrease in particle uptake. [Ca(2+)](i) chelation and PI-3 kinase inhibition reduce particle uptake by MØs, but are markedly less inhibitory in DCs. Thus, immature DCs appear to lack the Syt VII, Ca(2+) and PI-3 kinase-dependent forms of phagocytosis that are present in MØs. Interestingly, expression of Syt VII is up-regulated during LPS-induced DC maturation, a stimulus that also induces Syt VII translocation from intracellular compartments to the plasma membrane. Syt VII(-/-) DCs show a delayed translocation of MHC class II to the cell surface during maturation, consistent with the possibility that Syt VII facilitates exocytosis and/or surface retention of molecules critical for antigen presentation.
Assuntos
Sinalização do Cálcio , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Fagocitose , Sinaptotagminas/metabolismo , Animais , Apresentação de Antígeno , Diferenciação Celular , Separação Celular , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/patologia , Citometria de Fluxo , Lisossomos/metabolismo , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinaptotagminas/genética , Sinaptotagminas/imunologiaRESUMO
BACKGROUND: Hospital emergency department (ED) clinicians will play a crucial role in responding to any terrorist incident involving radioactive materials. To date, however, there has been a paucity of research focusing specifically on ED clinicians' perspectives regarding this threat. METHODS: At the request of the Centers for Disease Control and Prevention, researchers at the University of Alabama at Birmingham conducted a series of 10 focus groups (total participants, 77) with ED physicians and nurses at hospitals in 3 US regions. Participants considered a hypothetical "dirty bomb" scenario and discussed their perceptions, concerns, information needs, preferred information sources, and views of current guidance and informational materials. RESULTS: Study participants consistently expressed the view that neither EDs nor hospital facilities are sufficiently prepared for a terrorist event involving radioactive materials. Key clinician concerns included the possibility of the hospital being overwhelmed, safety of loved ones, potential staffing problems, readiness problems, and contamination and self-protection. Participants also expressed a need for additional information, strongly disagreed with aspects of current response guidance, and in some cases indicated they would not carry out current protocols. CONCLUSIONS: This study is the first to examine the views, perceptions, and information needs of hospital ED clinicians regarding radiological terrorism. As such, the findings may be useful in informing current and future efforts to improve hospital preparedness.
Assuntos
Atitude do Pessoal de Saúde , Planejamento em Desastres/organização & administração , Serviço Hospitalar de Emergência/organização & administração , Liberação Nociva de Radioativos , Terrorismo , Adulto , Descontaminação/métodos , Descontaminação/normas , Planejamento em Desastres/métodos , Feminino , Grupos Focais , Humanos , Masculino , Corpo Clínico Hospitalar/psicologia , Pessoa de Meia-Idade , Avaliação das Necessidades , Recursos Humanos de Enfermagem Hospitalar/psicologia , Exposição Ocupacional/prevenção & controle , Lesões por Radiação/terapia , Recursos HumanosRESUMO
Millions of people worldwide are currently infected with human papillomaviruses (HPVs). A therapeutic HPV vaccine would have widespread applicability because HPV-associated lesions are difficult to treat and may progress to carcinoma. We developed three attenuated VSV recombinants expressing the cottontail rabbit papillomavirus (CRPV) early protein E6 for use as vaccines. In cultured cells, two vectors expressed different levels of the E6 protein, and one expressed a ubiquitin-E6 fusion protein. All three were tested for therapeutic efficacy in the cottontail rabbit papillomavirus (CRPV)-rabbit model. Mock vaccination had no effect on papilloma growth. In contrast, inoculation with any of the VSV-E6 vaccines reduced the rate of papilloma growth to as little as 24% the rate in the controls. In five experiments, these effects were achieved after a single immunization. Furthermore, complete papilloma regression occurred in some rabbits observed for 4 months. A VSV-based papillomavirus E6 vaccine could have significant advantages over other therapeutic HPV vaccine candidates described to date.