Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for ...Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening.
This article aims to describe the activities conducted by the National Childhood Cancer Plan Working Group to support the development of national childhood cancer plans in Latin America and the ...Caribbean in the period 2019–2022, and to present the stage of plan development. The Working Group activities were supported by the Pan American Health Organization and St. Jude Children’s Research Hospital, which is the World Health Organization (WHO) Collaborating Centre for Childhood Cancer. Year after year, the workshops and activities developed with the Working Group mobilized key stakeholders: pediatric oncologists, representatives of the Ministry of Health, foundations supporting childhood cancer initiatives, and hospital administrators. As of February 2023, one regional framework is in place, approved by the Council of Ministries of Health of Central America and the Dominican Republic, nine countries are currently implementing national plans or laws that include childhood cancer, and ten countries are writing new plans. The WHO three-step framework helped to guide the Working Group activities. All plans were supported by a situational analysis, which highlighted the importance of having systematized data for evidence-based policies. To increase implementation success, an accompanying budget and timeline help to ensure the adequate implementation of the interventions. More than anything, committed stakeholders remain the most fundamental element to successfully write and approve a national childhood cancer plan. This is an opportunity to share these countries’ experience so the strategy can be adapted to support other countries developing a childhood cancer plan and extended to other public health areas.
This report describes the status of childhood cancer control initiatives in Latin America and the Caribbean (LAC). Progress between 2017 and 2023 is measured using the outcome indicators from the Pan ...American Health Organization (PAHO) childhood cancer logic model aligned with the World Health Organization Global Initiative for Childhood Cancer (GICC). This report also describes the advances, barriers, and facilitators for the implementation of the GICC at the Regional level. Methods used in this report encompassed a comprehensive approach, incorporating a literature review, interviews, surveys, and a Delphi study developed by the technical team of the PAHO Non-Communicable Diseases and Mental Health Department and by the GICC LAC working group. Since 2017, there has been a substantial increase in the number of countries that have included childhood cancer in their national regulations. Currently, 21 LAC countries are involved in the GICC implementation, activities, and dialogues. However, the objectives for 2030 will only be achieved if Member States overcome the barriers to accelerating the pace of initiative implementation. There is an urgent need to increase the efforts in childhood cancer control in LAC, especially regarding the prioritization of timely detection, essential diagnostics, access to cancer treatment, palliative care, and close follow-up of children and adolescents with cancer.
Working with PAHO/WHO to prioritize childhood cancer in the context of systems strengthening is central to St. Jude Children's Research Hospital (SJCRH)'s role as WHO Collaborating Centre for ...Childhood Cancer. This manuscript focuses on how SJCRH and PAHO/WHO have partnered to apply C5 (Country Collaboration for Childhood Cancer Control) to define and implement priority actions regionally, strengthening Ministry programs for childhood cancer, while implementing the Global Initiative for Childhood Cancer since 2018. Using C5, a tool developed by SJCRH, PAHO/WHO and SJCRH co-hosted regional/national workshops engaging authorities, clinicians and other stakeholders across 10 countries to map health systems needs and prioritize strategic activities (spanning Central America, Dominican Republic, Haiti, Brazil and Uruguay). SJCRH provided English/Spanish/Portuguese C5 versions/templates for analysis/prioritization exercises, and worked with PAHO/WHO and country teams to implement C5, analyze findings, and develop outputs. In an eight-country regional workshop, countries defined priorities within national/regional initiatives and ranked their value and political will, incorporating country-specific surveys and stakeholder dialogues. Each country prioritized one strategic activity for 2022-2023, exchanged insights via storytelling, and disseminated and applied results to inform country-specific and regional action plans. National workshops analyses have been incorporated into cancer control planning activities and collaborative work regionally. Implementation success factors include engaging actors beyond the clinic, enabling flexibility, and focusing on co-design with stakeholders. Joint implementation of C5 catalyzed prioritization and accelerated strategic activities to improve policies, capacity, and quality of care for children in the Americas, supporting Ministries to integrate childhood cancer interventions as part of systems strengthening. Keywords Cancer; health policy; health planning, health priorities; public health systems research; national health programs; child advocacy; adolescent health. La colaboracion con la OPS/OMS para priorizar el cancer infantil en el contexto del fortalecimiento de los sistemas es fundamental para la labor del St. Jude Children's Research Hospital (SJCRH) como centro colaborador de la OMS contra el cancer infantil. Este articulo se centra en la alianza entre el SJCRH y la OPS/OMS en la aplicacion de la herramienta C5 (colaboracion nacional para el control del cancer infantil) para definir y ejecutar medidas prioritarias a nivel regional, fortalecer los programas contra el cancer infantil del ministerio y poner en marcha la Iniciativa Mundial contra el Cancer Infantil desde el 2018. Con C5, una herramienta elaborada por el SJCRH, la OPS/OMS y este hospital organizaron conjuntamente talleres regionales y nacionales con autoridades, personal medico y otras partes interesadas en diez paises para determinar cuales son las necesidades de los sistemas de salud y priorizar las actividades estrategicas (en America Central, Republica Dominicana, Haiti, Brasil y Uruguay). El SJCRH proporciono versiones y plantillas de C5 en ingles, espanol y portugues para actividades de analisis y priorizacion y trabajo con la OPS/OMS y los equipos de pais para ejecutar la herramienta C5, analizar los resultados y elaborar productos. En un taller regional de ocho paises, se definieron las prioridades en las iniciativas regionales y nacionales, se clasifico su valor y la voluntad politica y se incorporaron encuestas especificas para cada pais y dialogos con las partes interesadas. Cada pais priorizo una actividad estrategica para el periodo 2022-2023, intercambio ideas por medio de narrativas, y difundio y aplico los resultados para fundamentar planes de accion tanto regionales como especificos para el pais. Los analisis de los talleres nacionales se han incorporado a las actividades de planificacion del control del cancer y al trabajo colaborativo a nivel regional. Entre los factores de exito de la ejecucion se encuentra involucrar a los agentes mas alla de lo clinico, permitir que haya flexibilidad y centrarse en un diseno elaborado en colaboracion con las partes interesadas. La ejecucion conjunta de la herramienta C5 catalizo la priorizacion y acelero las actividades estrategicas para mejorar las politicas, la capacidad y la calidad de la atencion infantil en la Region de las Americas y brindo apoyo a los ministerios para integrar las intervenciones contra el cancer infantil en el fortalecimiento de los sistemas. Palabras clave Cancer; politica de salud; planificacion en salud; prioridades en salud; investigacion en sistemas de salud publica; programas nacionales de salud; defensa del nino; salud del adolescente. A colaboracao com a OPAS/OMS para priorizar o cancer infantil no contexto do fortalecimento dos sistemas e fundamental para o papel do St. Jude Children's Research Hospital (SJCRH) como Centro Colaborador da OMS para o Cancer Infantil. Este artigo mostra como o SJCRH e a OPAS/OMS se associaram para aplicar a ferramenta C5 (Colaboracao Nacional para Controle do Cancer Infantil), com o proposito de definir e implementar acoes prioritarias regionalmente, fortalecendo programas ministeriais para o cancer na infancia, durante a implementacao da Iniciativa Global para o Cancer Infantil desde 2018. Com auxilio da C5, uma ferramenta desenvolvida pelo SJCRH, a OPAS/OMS e o SJCRH organizaram conjuntamente oficinas regionais/nacionais com a participacao de autoridades, profissionais de saude e outras partes interessadas em 10 paises, com a finalidade de mapear as necessidades dos sistemas de saude e priorizar atividades estrategicas (abrangendo America Central, Republica Dominicana, Haiti, Brasil e Uruguai). O SJCRH forneceu versoes/modelos da C5 em ingles, espanhol e portugues para exercicios de analise/priorizacao e colaborou com a OPAS/OMS e as equipes dos paises para implementar a C5, analisar resultados e desenvolver produtos. Em uma oficina regional com oito paises, foram definidas as prioridades das iniciativas nacionais/regionais e classificados seu valor e vontade politica, incorporando levantamentos nacionais e dialogos entre as partes interessadas. Cada pais priorizou uma atividade estrategica para 2022-2023, trocou conhecimentos por meio da narracao de historias e disseminou e aplicou os resultados para informar planos de acao nacionais e regionais. As analises das oficinas nacionais foram incorporadas as atividades de planejamento para controle do cancer e ao trabalho conjunto no ambito regional. Entre os fatores de exito da implementacao estao o engajamento de agentes de fora do segmento da saude, a oferta de flexibilidade e a enfase no planejamento conjunto com as partes interessadas. A implementacao conjunta da C5 catalisou a priorizacao e acelerou atividades estrategicas para aprimorar as politicas, a capacidade e a qualidade da atencao as criancas nas Americas, apoiando os ministerios na integracao das intervencoes contra o cancer infantil como parte do fortalecimento dos sistemas. Palavras-chave Cancer; politica de saude; planejamento em saude; prioridades em saude; pesquisa em sistemas de saude publica; programas nacionais de saude; defesa da crianca e do adolescente; saude do adolescente
ABSTRACT Human cytomegalovirus (HCMV) pathogenesis is dependent on the hematogenous spread of the virus to host tissue. While data suggest that infected monocytes are required for viral dissemination ...from the blood to the host organs, infected endothelial cells are also thought to contribute to this key step in viral pathogenesis. We show here that HCMV infection of endothelial cells increased the recruitment and transendothelial migration of monocytes. Infection of endothelial cells promoted the increased surface expression of cell adhesion molecules (intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, E-selectin, and platelet endothelial cell adhesion molecule 1), which were necessary for the recruitment of naïve monocytes to the apical surface of the endothelium and for the migration of these monocytes through the endothelial cell layer. As a mechanism to account for the increased monocyte migration, we showed that HCMV infection of endothelial cells increased the permeability of the endothelium. The cellular changes contributing to the increased permeability and increased naïve monocyte transendothelial migration include the disruption of actin stress fiber formation and the decreased expression of lateral junction proteins (occludin and vascular endothelial cadherin). Finally, we showed that the migrating monocytes were productively infected with the virus, documenting that the virus was transferred to the migrating monocyte during passage through the lateral junctions. Together, our results provide evidence for an active role of the infected endothelium in HCMV dissemination and pathogenesis.
Type I phosphatidylinositol 4-phosphate 5-kinase (PI4P5K) catalyzes the phosphorylation of phosphatidylinositol 4 phosphate PI(4)P at carbon 5, producing phosphatidylinositol 4,5 bisphosphate ...PI(4,5)P2. Phosphatidic acid (PA) activates PI4P5K in vitro and plays a central role in the activation of PIP5K pathways in vivo. This report demonstrates that actin fiber formation in murine fibroblasts involves PA activation of PIP5Ks and defines biochemical interactions between PA and the PIP5Ks. Inhibition of phospholipase D production of PA results in the loss of actin fibers. Overexpression of the beta isoform of the type I murine phosphatidylinositol 4-phosphate 5-kinase (mPIP5K-Ibeta) maintains actin fiber structure in the face of phospholipase D inhibition. PA activates mPIP5K-Ibeta by direct binding to mPIP5K-Ibeta through both electrostatic and hydrophobic interactions, with the fatty acid acyl chain length and degree of saturation acting as critical determinants of binding and activation. Furthermore, kinetic analysis suggests that phosphorylation of the PI(4)P substrate does not follow classical Michaelis-Menten kinetics. Instead, the kinetic data are consistent with a model in which mPIP5K-Ibeta initially binds to the lipid micelle and subsequently binds the PI(4)P substrate. In addition, the kinetics indicate substrate inhibition, suggesting that mPIP5K-Ibeta contains an inhibitory PI(4)P-binding site. These results suggest a model in which mPIP5K-Ibeta is surrounded by PI(4)P, but is unable to catalyze its conversion to PI(4,5)P2 unless PA is bound.
eIF4E is essential for translation initiation, but its overexpression causes malignant transformation. Recent work demonstrated that eIF4E/F participates in exposing and locating alternate ...translation start codons during scanning. Translation initiation of several important protooncogenes and growth-regulators, such as Myc and FGF-2, can start at CUG start codon(s) upstream of the normal open reading frame (ORF). The resulting amino-terminal extension alters the properties of these proteins and their intracellular distribution. In cells overexpressing eIF4E, c-myc is overexpressed and particularly the larger, CUG-initiated form (Myc1). Recent reports suggest that synthesis of Myc2, the normally expressed AUG-initiated form, is mediated by an IRES. To determine what role eIF4E might play in c-myc expression, the c-myc 5' untranslated region (UTR) was fused in-frame to CAT reporters, and several more derivative constructs were made. In vitro translation experiments (with and without eIF4E/F); expression in CHO cells transformed with eIF4E; and deletion/mutation analysis demonstrated that Myc1 is translated by a scanning mechanism, while Myc2 is translated by Internal Ribosome Repositioning. Moreover, the existence of a true IRES in the 5'UTR was contradicted by its failure to direct translation of a circular transcript, in contrast to hsp70. The c-myc 5'UTR also failed to engage in translation in the absence of functional eIF4F, after cleavage of the eIF4G component with CVB4 protease-2A. The Internal Repositioning Element (IRPE) in c-myc 5'UTR was delimited to nucleotides (nt) 394-440 from the P1 transcription start site.
eIF4E is essential for translation initiation, but its overexpression causes malignant transformation. Recent work demonstrated that eIF4E/F participates in exposing and locating alternate ...translation start codons during scanning. Translation initiation of several important protooncogenes and growth-regulators, such as Myc and FGF-2, can start at CUG start codon(s) upstream of the normal open reading frame (ORF). The resulting amino-terminal extension alters the properties of these proteins and their intracellular distribution. In cells overexpressing eIF4E, c-myc is overexpressed and particularly the larger, CUG-initiated form (Myc1). Recent reports suggest that synthesis of Myc2, the normally expressed AUG-initiated form, is mediated by an IRES. To determine what role eIF4E might play in c-myc expression, the c-myc 5′ untranslated region (UTR) was fused in-frame to CAT reporters, and several more derivative constructs were made. In vitro translation experiments (with and without eIF4E/F); expression in CHO cells transformed with eIF4E; and deletion/mutation analysis demonstrated that Myc1 is translated by a scanning mechanism, while Myc2 is translated by Internal Ribosome Repositioning. Moreover, the existence of a true IRES in the 5′UTR was contradicted by its failure to direct translation of a circular transcript, in contrast to hsp70. The c-myc 5′UTR also failed to engage in translation in the absence of functional eIF4F, after cleavage of the eIF4G component with CVB4 protease-2A. The Internal Repositioning Element (IRPE) in c-myc 5′UTR was delimited to nucleotides (nt) 394 – 440 from the P1 transcription start site.
PDF
